U.S. patent number 5,874,573 [Application Number 08/669,698] was granted by the patent office on 1999-02-23 for compounds with chelation affinity and selectivity for first transition series elements: use in medical therapy.
This patent grant is currently assigned to Concat, Inc.. Invention is credited to Rosa L Cyjon, Joseph Y Klein, Ofer Klein, Elliot D Simhon, Harry S Winchell, Haim Zaklad.
United States Patent |
5,874,573 |
Winchell , et al. |
February 23, 1999 |
**Please see images for:
( Certificate of Correction ) ** |
Compounds with chelation affinity and selectivity for first
transition series elements: use in medical therapy
Abstract
This invention involves synthesis and use of a class of
compounds with chelation affinity and selectivity for first
transition series elements. Administration of the free or
conjugated compound, or physiological salts of the free or
conjugated compound, results in decrease in the in vivo
bioavailability of first transition series elements and/or removal
from the body of first transition series elements and elements with
similar chemical properties. These characteristics make such
compounds useful in the management of diseases associated with a
bodily excess of first transition series elements and elements with
similar chemical properties. This invention demonstrates that such
compounds inhibit mammalian, bacterial, and fungal cell replication
and are therefore useful in the treatment of neoplasia, infection,
inflammation, immune response, and in termination of pregnancy.
Since these compounds are capable of descreasing the in vivo
availability of tissue iron they are useful in management of free
radical mediated tissue damage, and oxidation mediated tissue
damage. When combined with radioisotopic or paramagnetic cations of
first transition series elements, or elements with chemical
properties similar to those of first transition series elements,
prior to their administration, the resulting complexes are useful
as diagnostic agents in nuclear medicine and magnetic resonance
imaging (MRI).
Inventors: |
Winchell; Harry S (Lafayette,
CA), Klein; Joseph Y (Haifa, IL), Simhon; Elliot
D (Haifa, IL), Cyjon; Rosa L (Haifa,
IL), Klein; Ofer (Haifa, IL), Zaklad;
Haim (Haifa, IL) |
Assignee: |
Concat, Inc. (Concord,
CA)
|
Family
ID: |
26667775 |
Appl.
No.: |
08/669,698 |
Filed: |
June 24, 1996 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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560626 |
Nov 20, 1995 |
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Current U.S.
Class: |
540/465; 540/145;
540/474 |
Current CPC
Class: |
A61P
19/10 (20180101); C07D 487/08 (20130101); A61P
39/06 (20180101); A61K 31/4025 (20130101); A61P
37/06 (20180101); A61K 31/395 (20130101); A61K
31/415 (20130101); A61K 47/54 (20170801); A61K
49/04 (20130101); C07D 255/02 (20130101); A61K
31/135 (20130101); A61P 31/14 (20180101); C07D
405/14 (20130101); C07D 487/10 (20130101); C07D
255/04 (20130101); A61K 51/0478 (20130101); A61K
31/13 (20130101); A61P 7/00 (20180101); A61P
17/00 (20180101); A61K 31/131 (20130101); A61P
29/00 (20180101); A61K 49/06 (20130101); A61P
31/00 (20180101); A61P 35/00 (20180101); C07F
9/6561 (20130101); A61P 17/02 (20180101); C07F
9/6515 (20130101); C07F 9/6524 (20130101); A61K
31/136 (20130101); A61K 51/0482 (20130101); A61P
39/04 (20180101); A61K 49/0002 (20130101); C07D
257/00 (20130101); C07D 403/14 (20130101); A61K
47/547 (20170801); A61P 3/00 (20180101); A61K
31/137 (20130101); A61K 31/44 (20130101); A61P
31/04 (20180101); A61K 31/675 (20130101); A61P
31/10 (20180101); Y10S 514/836 (20130101) |
Current International
Class: |
A61K
31/44 (20060101); A61K 31/675 (20060101); C07D
405/14 (20060101); C07D 403/14 (20060101); C07D
405/00 (20060101); A61K 31/13 (20060101); A61K
31/135 (20060101); A61K 31/137 (20060101); A61K
31/131 (20060101); A61K 31/136 (20060101); A61K
49/00 (20060101); C07D 255/00 (20060101); C07D
255/02 (20060101); A61K 47/48 (20060101); C07D
257/00 (20060101); A61K 49/04 (20060101); C07D
255/04 (20060101); A61K 49/06 (20060101); A61K
51/04 (20060101); A61K 51/02 (20060101); C07F
9/00 (20060101); C07F 9/6524 (20060101); C07F
9/6515 (20060101); C07D 403/00 (20060101); A61K
31/415 (20060101); A61K 31/395 (20060101); C07F
9/6561 (20060101); C07D 487/08 (20060101); C07D
487/22 (20060101); A61K 31/4025 (20060101); C07D
487/00 (20060101); C07D 487/10 (20060101); C07B
047/00 (); C07D 225/00 (); C07D 255/02 () |
Field of
Search: |
;540/465,474,145 |
References Cited
[Referenced By]
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WO |
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WO |
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WO |
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T.M. Jones-Wilson et al. "New Hydroxybenzyl and
Hydroxypyridylmethyl Substituted Triazacyclononane Ligands for Use
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.
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Primary Examiner: Shah; Mukund J.
Assistant Examiner: Ngo; Tamthom T.
Attorney, Agent or Firm: Townsend and Townsend and Crew
LLP
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATION
This application is related to provisional application Ser. No.
60/000,524, filed Jun. 26, 1995, and is also a continuation-in-part
of 08/560,626 filed Nov. 20, 1995, each of which is incorporated by
reference herein for all legal purposes to be served thereby.
Claims
What is claimed is:
1. A pharmaceutical composition for use in medical therapy
comprising:
(A) a chelating agent capable of complexing first transition series
elements but not itself so complexed, said chelating agent having
the formula: ##STR215## wherein, t, u and v are each independently
2 or 3;
w is an integer of from 1 to 3;
R.sup.12 and R.sup.13 are each independently selected from the
group consisting of H, allyl, alkenyl, aryl, arylalkyl, alkoxy,
alkylthio, alkenoxy, alkenylthio, aryloxy, arylthio, alkyl
interrupted by one or more oxa, alkenyl interrupted by one or more
oxa, alkyl interrupted by thia, alkenyl interrupted by thia,
aryloxyalkyl, alkoxyaryl, aminoalkyl, aminoalkenyl, aminoaryl,
aminoarylalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyaryl,
hydroxyarylaLkyl, halogen substituted versions thereof;
R.sup.11 is a member selected from the group consisting of
R.sup.12, R.sup.13 and radicals of formula: ##STR216## wherein,
R.sup.41, R.sup.42 and R.sup.43 are each independently selected
from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl,
alkoxy, alkylthio, alkenoxy, alkenylthio, aryloxy, arylthio, alkyl
interrupted by oxa, alkenyl interrupted by oxa, alkyl interrupted
by thia, alkenyl interrupted by thia, aryloxyalkyl, alkoxyaryl,
aminoalkyl, aminoalkenyl, aminoaryl, aminoarylalkyl, hydroxyalkyl,
hydroxyalkenyl, hydroxyaryl, hydroxyarylalkyl, and halogen
substituted versions thereof;
R.sup.44 is a member selected from the group consisting of H,
hydroxy, amino, alkyl, alkyl interrupted by oxa, alkoxy, aryl,
aryloxyalkyl, alkoxyaryl, and halogen substituted versions
thereof;
n is zero or 1; and
X is a member selected from the group consisting of alkyl, alkenyl,
aryl, arylalkyl, alkoxy, alkylthio, alkenoxy, aryloxy, arylthio,
alkyl interrupted by one or more oxa, alkenyl interrupted by one or
more oxa, alkyl interrupted by one or more thia, alkenyl
interrupted by one or more thia, aryloxyalkyl, alkoxyaryl,
aminoalkyl, aminoalkenyl, aminoaryl, aminoarylalkyl, hydroxyalkyl,
hydroxyalkenyl, hydroxyaryl hydroxyarylalkyl, halogen substituted
versions of each of the above, and radicals selected from the group
consisting of: ##STR217## wherein R.sup.41, R.sup.42, R.sup.43 and
R.sup.44 are each independently as described above;
R.sup.46 and R.sup.47 are each independently selected from the
group consisting of H, alkyl and aryl, or taken together form a
divalent linking group between the atoms to which they are
attached, thereby forming a ring structure;
R.sup.48 and R.sup.49 are each independently selected from the
group consisting of H, alkyl, aryl, alkoxy, alkyl interrupted by
oxa, aryloxyalkyl, alkoxyaryl, and halogen substituted versions
thereof;
R.sup.50, R.sup.51 and R.sup.52 are each independently selected
from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl,
alkyloxy, alkylthio, alkenyloxy, alkenylthio, aryloxy, arylthio,
amninoalkyl, aminoalkenyl, aminoaryl, aminoarylalkyl, hydroxyalkyl,
hydroxyalkenyl, hydroxyaryl, and hydroxyarylalkyl; and m is an
integer of from 1 to 3,
and wherein, optionally, any two of R.sup.11, R.sup.12 and R.sup.13
are combined to form a ring structure; and dimers formed by the
covalent attachment of two compounds of formula (II) in which w is
1, through a linking group having from 1 to 6 carbon atoms;
and physiological salts thereof, with the proviso that the
molecular weight of said chelating agent does not exceed 2000;
and
(B) a pharmaceutically acceptable carrier.
2. A pharmaceutical composition in accordance with claim 1 wherein
w is 1 or 2.
3. A pharmaceutical composition in accordance with claim 1 wherein
w is 1 and t, u, and v are all 2.
4. A pharmaceutical composition in accordance with claim 3 wherein
R.sup.11 is a radical of formula: ##STR218## and X is an acidic
group or a physiological salt thereof.
5. A pharmaceutical composition in accordance with claim 4, wherein
X is PO.sub.3 H.sub.2.
6. A pharmaceutical composition in accordance with claim 4, wherein
n is 0 and X is PO.sub.3 H.sub.2.
7. A pharmaceutical composition in accordance with claim 3, wherein
R.sup.12 and R.sup.13 are both H.
8. A pharmaceutical composition in accordance with claim 1, wherein
X is PO(OH)(OR.sup.47).
9. A pharmaceutical composition in accordance with claim 1, wherein
n is 0 and X is PO(OH)(OR.sup.47).
10. A pharmaceutical composition in accordance with claim 4,
wherein X is CO.sub.2 H.
11. A pharmaceutical composition in accordance with claim 4,
wherein n is 0 and X is CO.sub.2 H.
12. A pharmaceutical composition in accordance with claim 3,
wherein one R.sup.11 group is the same as either R.sup.12 or
R.sup.13, and the remaining R.sup.11 groups are of formula (V).
13. A pharmaceutical composition in accordance with claim 12,
wherein n is 0 and X is PO.sub.3 H.sub.2.
14. A pharmaceutical composition in accordance with claim 12,
wherein n is 0 and X is PO(OH)(OR.sup.47).
15. A pharmaceutical composition in accordance with claim 12,
wherein n is 0 and X is CO.sub.2 H.
16. A pharmaceutical composition in accordance with claim 12
wherein R.sup.11 is selected from the group consisting of alkyl,
.beta.-hydroxyalkyl, alkenyl, .beta.-hydroxyalkenyl, aryl,
arylalkyl, .beta.-hydroxyarylalkyl, cycloalkyl and
.beta.-hydroxycycloalkyl.
17. A pharmaceutical composition in accordance with claim 16
wherein the .beta.-hydroxysubstituted radicals are further
substituted at the .beta.-position with one or more members
selected from the group consisting of hydroxymethyl, alkoxymethyl,
alkenoxymethyl, aryloxymethyl and combinations thereof.
18. A pharmaceutical composition in accordance with claim 16
wherein the .beta.-hydroxysubstituted radicals are further
substituted with one or more halogen atoms.
19. A pharmaceutical composition in accordance with claim 12
wherein R.sup.11 is selected from the group consisting
2-hydroxy-(2,2-diisopropoxymethyl)ethyl and
(3-hydroxy-6,6,7,7-tetramethyl-1,5-dioxacyclohept-3-yl)methyl.
20. A pharmaceutical composition in accordance with claim 12
wherein the molecular weight of said compound is from 400 to
1100.
21. A pharmaceutical composition in accordance with claim 1 wherein
said chelating agent is a member selected from the group consisting
of
1,2-Bis(1,4,7-triazabicyclononan-1-yl)ethane,
N,N',N"-Tris(2-hydroxy-3-isopropoxypropyl)-1,4,7-triazacyclononane,
(R, R, R)
N,N',N"-Tris(2-hydroxy-3-isopropoxypropyl)-1,4,7-triazacyclononane,
(S, S, S)
N,N',N"-Tris(2-hydroxy-3-isopropoxypropyl)-1,4,7-triazacyclononane,
N,N',N"-Tris(2-hydroxy-3-butoxypropyl)-1,4,7-triazacyclononane,
(R, R, R)
N,N',N"-Tris(2-hydroxy-3-isobutoxypropyl)-1,4,7-triazacyclononane,
N,N',N"-Tris(2-hydroxy-3-methoxypropyl)-1,4,7-triazacyclononane,
N,N',N"-Tris(2,3-dihydroxypropyl)-1,4,7-triazacyclononane,
N,N',N"-Tris(2-hydroxy-3-allyloxypropyl)-1,4,7-triazacyclononane,
N,N',N"-Tris(2-hydroxy-3-phenoxypropyl)-1,4,7-triazacyclononane,
N,N',N"-Tris(2-hydroxy-2,2-diethoxymethylene)ethyl-1,4,7-triazacyclononane,
N,N',N"-Tris(2-hydroxy-2,2-dimethoxymethyl)ethyl-1,4,7-triazacyclononane,
N,N',N"-Tris(2-hydroxy-2,2-diisopropyloxymethyl)ethyl-1,4,7-triazacyclonona
ne,
N,N',N"-Tris(2-hydroxy-bis(2-furfuryhnethyl)ethyl)-1,4,7-triazacyclononane,
N,N',N"-Tris(3-hydroxy-1,5-dioxacycloheptyl-3-methyl)-1,4,7-triazacyclonona
ne,
N,N',N"-Tris((3-Hydroxy-7,7-dimethyl-1,5-dioxacyclooct-3-yl)-methyl)-1,4,7-
triazacyclononane,
N,N',N"-Tris((3-hydroxy-7-methyl-1,5-dioxacyclohept-3-yl)methyl)-1,4,7-tria
zacyclononane,
N,N',N"-Tris((3-hydroxy-6,6,7,7-tetramethyl-1,5-dioxacyclohept-3-yl)methyl)
-1,4,7-triazacyclononane,
N,N',N"-Tris((3-hydroxy-benzo(b)-1,5-dioxacycloheptyl)methyl)
1,4,7-triazacyclononane,
N,N',N"-Tris((3-hydroxy-1,5-dioxacyclooctan-3-yl)methyl)-1,4,7-triazacyclon
onane,
N,N',N"-Tris((4-fluoro-2-hydroxy-3-isopropyl-4-methyl)pentyl)-1,4,7-triazac
yclononane,
N,N',N"-Tris-(2-hydroxy-3-(1-fluoroethyl)-4-hydroxypentyl)-1,4,7-triazacycl
ononane,
N,N',N"-Tris(2-hydroxy-2-(1-fluoroethyl)-2-(1-methoxyethyl)ethyl)-1,4,7-tri
azacyclononane,
N,N',N"-Tris(2-hydroxy-2-ethyl-3-methoxybutyl)-1,4,7-triazacyclononane,
N,N',N"-Tris((2,3-dihydroxy-2-ethyl)butyl)-1,4,7-triazacyclononane,
N,N',N"-Tris(2-hydroxy-2,2-bis(1-fluoroethyl)ethyl)-1,4,7-triazacyclononane
N,N',N"-Tris(2-hydroxy-2,2-bis(1-methoxyethyl)ethyl)-1,4,7-triazacyclononan
e,
N,N',N"-Tris((3,3-dimethyl-2-hydroxy)butyl)-1,4,7-triazacyclononane,
N,N',N"-Tris(2-hydroxycyclohexan-1-yl)-1,4,7-triazacyclononane,
N,N',N",N"'-Tetrakis(2,3-dihydroxypropyl)-1,4,7,
10-tetraazacyclotetradecane,
4.
10-Bis(2-hydroxypropyl)-1,4,7,10-tetraazabicyclo(5.5.2)tetradecane,
4,10-Bis-(2-hydroxyethyl)-1,4,7,10-tetrazabicyclo(5.5.2)tetradecane,
4,10-Bis-(2,3-dihydroxypropyl)-1,4,7,10-tetraazabicyclo(5.5.2)tetradecane,
N,N',N"-Tris((2,4-dihydroxy-3-isopropyl-4-methyl)pentyl)-1,4,7-triazacyclon
onane,
N,N',N"-Tris(2-hydroxy-2,2-di(hydroxymethyl)ethyl)-1,4,7-triazacyclononane,
N,N',N"-Tris(dihydroxyphosphoryl mono butyl
ester)methyl-1,4,7-triazacyclononane,
N,N',N"-Tris(dihydroxyphosphorylmethyl monoethyl
ester)-1,4,7-triazacyclononanc.,
N,N',N"-Tris(dihydroxyphosphorylmethyl monooctyl
ester)-1,4,7-triazacyclononane,
N,N',N"-Tris(dihydroxyphosphorylmethyl monoisobutyl
ester)-1,4,7-triazacyclononane,
1.
2-Bis(N,N'-bis(dihydroxyphosphorylmethyl)-1,4,7-triazacyclononan-1-yl)et
hane,
1,2-Bis(N,N'-bis(dihydroxyphosphorylmethyl)-1,4,7-triazacyclononan-1-yl)pro
pane,
4,10-Bis(dihydroxyphosphorylmethyl)-1,4,7,10-tetraazabicyclo(5.5.2)
tetradecane,
4,7,13-Tris(dihydroxyphosphorylmethyl)-1,4,7,10,13-pentaazabicyclo(8.5.2)he
ptadecane,
N,N',N"-Tris(dihydroxyphosphorylethyl)-1,4,7-triazacyclononane,
N',N",N"',N""-Tetrakis(dihydroxyphosphorylethyl)-1,4,7,10-tetraazacyclodode
cane,
4,10-Bis(dihydroxyphosphorylethyl)-1,4,7,10-tetraazabicyclo(5.5.2)
tetradecane,
N,N',N"-Tris((N-methyl-N-hydroxycarbamoyl)methyl)-I
,4,7-triazacyclononane,
N,N',N"-Tris((N-isopropyl-N-hydroxycarbamoyl)methyl)-1,4,7-triazacyclononan
e,
N,N',N"-Tris((N-t-butyl-N-hydroxycarbamoyl)methyl)-1,4,7-triazacyclononane,
N,N',N"-Tris((N-hydroxycarbamoyl)methyl)-1,4,7-triazacyclononane,
N,N',N"-Tris((N-methoxycarbamoyl)methyl)-1,4,7-triazacyclononane,
4.
10-Bis((N-hydroxy-N-methylcarbamoyl)methyl)-1,4,7,10-tetraazabicyclo(5.5
.2)tetradecane,
N,N',N"-Tris((1-oxy-2-pyrrolidon-5-yl)methyl)-1,4,7-triazacyclononane,
N,N',N"-Tris(carboxymethyl)-1,4,7-triazacyclononane,
1,2-Bis-(4,7-carboxymethyl-1,4,7-triazacyclononan-1-yl)ethane,
N,N',N"-Tris(carboxyethyl)-1,4,7-triazacyclononane,
4,10-Bis(carboxymethyl)-1,4,7,10-tetraazabicyclo(5.5.2)tetradecane,
N,N',N"-Tris(2,2-dimethoxyethyl)-1,4,7-triazacyclononane,
N,N',N"-Tris(pyrrol-2-yl-methyl)-1,4,7-triazacyclononane,
N,N',N"-Tris(N-n-butyl(carbamoylmethyl))-1,4,7-triazacyclononane,
N,N',N"-Tris(N-phenyl(carbamoylmethyl))-1,4,7-triazacyclononane,
4,7-Bis(2-hydroxybenzyl)-1,4,7,10-tetraazabicyclo(5.5.2)tetradecane,
N,N'-Bis-(2,2'-dihydroxybiphenylmethyl)diethylenetriamine,
N,N'-Bis-(2,2'-tetrahydroxybiphenylmethyl)-1,3-diaminopropane,
N,N',N"-Tris(2-hydroxybenzyl)-1,4,7-triazacyclononane,
N,N'-bis(dihydroxyphosphorylnethyl)-1,4,7-triazacyclononane,
N-(carboxymethyl)-N',N"-bis(dihydroxyphosphorylmethyl)-1,4,7-triazacyclonon
ane,
N,N',N"-Tris(2-dihydroxyphosphoryl-1-hydroxy)ethyl)-1,4,7-triazacyclononane
N,N'-Bis-(2,2'-dihydroxybiphenylmethyl)ethylenediamine,
N,N'-Bis-(2,4-tetrahydroxybiphenylmethyl)ethylenediamine,
1. 4,7,10-Tetraazabicyclo(5.5.2)tetradecane,
4,7-Bis(carboxymethyl)-1,4,7,10-tetraazabicyclo(5.5.2)tetradecane,
N,N',N"-Tris(2-hydroxy-2-methylpropyl)-1,4,7-triazacyclononane,
N,N',N"-Tris(2-hydroxypropyl)-1,4,7-triazacyclononane,
N,N',N"-Tris(((diethylphosphoryl)-.alpha.-hydroxy)ethyl)-1,4,7-triazacyclon
onane,
N,N',N"-Tris(1-methoxy-2-hydroxy-2-methylpropyl)-1,4,7-triazacyclononane,
N,N',N"-Tris(2-hydroxycyclopentane-1-yl)-1,4,7-triazacyclononane,
N,N',N"-Tris((3-chloro-2-hydroxy)propyl)-1,4,7-triazacyclononane,
1,2-Bis(N,N'-di-2-hydroxyethyl-1,4,7-triazacyclononane-1-yl)ethane,
N,N',N"',
N""-Tetrakis(2-hydroxyethyl)-1,4,7,10-tetraazacyclododecane,
4,10-Bis((2-hydroxy-2-phenyl)ethyl)-1,4,7,10-tetraazabicyclo(5.5.2)tetradec
ane,
N,N',N'",N""-Tetrakis(2,3-dihydroxypropyl)-1,4,8,11-tetraazacyclohexadecane
N,N',N"-Tris(.alpha.-dihydroxyphosporyl-.alpha.-benzyl)methyl)-1,4,7-triaza
cyclononane,
N,N',N"-Tris(1-oxy-2-pyrrolidone-5-yl)-1,4,7-triazacyclononane,
N,N',N"-Tris(.alpha.-methylcarboxymethyl)-1,4,7-triazacyclononane,
N,N',N"-Tris(2-aminoethyl)-1,4,7-triazacyclononane,
N,N',N"-Tris(methylcarboxamide)-1,4,7-triazacyclononane,
4-(2-hydroxy-benzyl)-1,4,7,10-tetraazabicyclo(5.5.2)tetradecane,
and
4-(2-hydroxy-benzyl)-7-phosphorylethyl-1,4,7,10-tetraazabicyclo(5.5.2)tetra
decane.
Description
The present invention lies in the field of metal cation chelators
(ligands) and their use for purposes of decreasing the
bioavailability of elements of the first transition series, and/or
the removal from the body of these elements or those with similar
chemical properties. First transition series elements are
components of enzymes required for nucleic acid replication as well
as general cell replication. By inhibiting nucleic acid replication
these agents are useful in inhibiting growth of DNA and RNA
viruses. By inhibiting bacterial and fungal cell replication these
agents are useful in vitro as preservatives, and employing topical
or systemic in vivo administration they are useful in treating
bacterial and fungal infections and in wound care. By inhibiting
protozoan cell replication these agents are useful in treatment of
protozoan infections. By inhibiting mammalian cell replication,
these agents are useful in treating neoplastic disease, in
suppression of the immune response, in inhibition of osteoclast
activity, and in termination of pregnancy. Iron, a first transition
element, is involved in free radical mediated tissue damage. By
decreasing the body free iron content, these agents inhibit free
radical mediated tissue damage. Excess of body iron characterizes
hemochromatosis/hemosiderosis, and excess of the first transition
series element, copper, characterizes Wilson's disease. By removing
either excess iron or copper from the body these agents are useful
in treating these diseases. When combined with elements possessing
paramagnetic properties, the chelating agents described herein also
find diagnostic utility as contrast enhancing agents in magnetic
resonance imaging. When combined with radioactive elements, these
chelating agents find utility in nuclear medical imaging.
BACKGROUND OF THE INVENTION
Metal cations belonging to the first transition series are known to
play important coenzymatic roles in metabolism. Zinc is known to be
a coenzyme for over eighty different enzyme systems including those
directly involved with DNA and RNA synthesis such as thymidine
kinase, DNA and RNA polymerases, reverse transcriptase and terminal
deoxynucleotide transferase. Among its other coenzyme functions,
iron is the coenzyme for myoglobin, the cytochromes and catalases
and is thus essential for oxidative metabolism. Manganese and
copper also play significant coenzyme roles, and other metal
cations in the first transition series are considered to be
essential trace elements although their metabolic role is less well
defined.
Compounds capable of forming complexes with metal cations, which
compounds are commonly referred to as chelators or ligands, are
known to have a variety of uses in medicine. These include their
use as pharmaceuticals in treating heavy metal poisoning, in
treating diseases associated with trace metal excess such as iron
storage and copper storage diseases (hemosiderosis and Wilson's
disease, respectively), as radiopharmaceutical agents in nuclear
medical imaging when forming complexes with radioactive metals, as
contrast enhancement agents in magnetic resonance imaging (MRI)
when forming complexes with paramagnetic metals, and as contrast
enhancement agents in radiography when forming complexes with heavy
metals.
Examples of ligands employed in treating heavy metal poisoning such
as that due to lead, mercury, and other metals, are ethylenediamine
tetraacetic acid (EDTA) and diethylenetriamine pentaacetic acid
(DTPA). The ligand desferrioxamine is used in treating iron storage
disease, and the ligand penicillamine is used in the mobilization
of copper in the treatment of Wilson's disease.
Examples of complexes used to form radiopharmaceuticals useful in
evaluations of the kidneys, bone and liver are complexes of
technetium-99m (.sup.99m Tc) with diethylenetriamine pentaacetic
acid (DTPA), dimercaptosuccinic acid (DMSA), methylene
diphosphonate (MDP) and derivatives of iminodiacetic acid
(IDA).
Complexes of paramagnetic metal cations which are useful as MRI
contrast agents operate by accelerating proton relaxation rates.
Most commonly a metal cation, such as gadolinium (III), having a
large number of unpaired electrons is complexed by a ligand
suitable for complexation of that cation. An example is gadolinium
(III) complexed by DTPA.
Chelators with affinity for iron cations have been shown to inhibit
cell proliferation. Desferrioxamine is one example of such a
chelator. This effect is thought to be a consequence of the
complexation of tissue iron by the chelator, which thereby deprives
the proliferating cells of a source of iron for critical enzyme
synthesis. Moreover, it is believed that certain types of tissue
damage are mediated by the formation of free radicals. It is also
appreciated that catalytically active iron catalyzes formation of
the highly active hydroxyl free radical. Based on such
relationships chelators (ligands) for iron such as desferrioxamine
and the experimental iron chelator "L1"
(1,2-dimethyl-3-hydroxypyrid-4-one) have been examined in
management of conditions where free radical mediated tissue damage
is believed to play a role, as well as in clinical management of
conditions in which control of cell proliferation is desired.
Conditions where the administration of iron chelators has been
evaluated include: rheumatoid arthritis, anthracycline cardiac
poisoning, reperfusion injury, solid tumors, hematologic cancers,
malaria, renal failure, Alzheimer's disease, myelofibrosis,
multiple sclerosis, drug-induced lung injury, graft versus host
disease, and transplant rejection and preservation (Voest, E. E.,
et al., "Iron Chelating Agents in Non-Iron Overload conditions,"
Annals of Internal Medicine 120(6): 490-499 (15 March 1994)).
Agents which inhibit cell replication have found use in the prior
art as chemotherapeutic agents for treatment of neoplasia and
infectious disease, for suppression of the immune response, and for
termination of pregnancy.
Such agents usually act by inhibiting DNA, RNA or protein
synthesis. This results in a greater adverse effect on rapidly
proliferating cell populations than on cells "resting" in
interphase or proliferating less rapidly.
Such agents may possess a degree of selectivity in treating the
rapidly proliferating offending cell population, particularly in
the case of certain neoplasias and infectious processes. These
agents also inhibit replication of normal cells of the host
organism, to varying degrees. Cells of the immune system
proliferating in response to antigenic challenge are sensitive to
such agents, and accordingly these agents are useful in suppressing
the immunological response. Examples are the suppression of the
homograft rejection response following tissue transplantation and
the treatment of autoimmune disorders. Replication of protozoan,
bacterial and mycotic microorganisms are also sensitive to such
agents, which makes the agents useful in treating infections by
such microorganisms.
Agents which suppress cell replication by inhibiting DNA or RNA
synthesis have primarily found utility in treatment of neoplastic
diseases. The glutamine antagonists azaserine, DON, and the
anti-purines such as 6-mercaptopurine and 6-thioguanine principally
inhibit DNA synthesis by their action on
phosphoribosylpyrophosphate amidotransferase, the enzyme involved
in the first step in purine nucleotide synthesis. The folic acid
antagonists aminopterin and methotrexate inhibit DNA synthesis (and
other synthetic processes involving one carbon transport) by
inhibiting the dihydrofolate reductase enzyme system, thereby
interfering with formation of tetrahydrofolate, which is necessary
in transfer of one-carbon fragments to purine and pyrimidine rings.
Hydroxyurea inhibits DNA synthesis by inhibiting ribonuclease
reductase, thereby preventing reduction of ribonucleotides to their
corresponding deoxyribonucleotides. The anti-pyrimidines such as
5-fluorouracil inhibit DNA synthesis by inhibiting thymidylate
synthetase. 5-Fluorouracil may also be incorporated into fraudulent
RNA molecules. Bleomycin appears to inhibit DNA synthesis by
blocking thymidine incorporation into DNA, although it may have
other mechanisms of action. Agents such as 5-bromouracil and
iododeoxyuridine may be incorporated into DNA in place of
thymidine, and cytosine arabinoside may be incorporated into DNA in
place of 2'-deoxycytidine. The fraudulent DNA produced by these
incorporations interferes with the information transmittal system
for DNA.fwdarw.RNA.fwdarw.protein synthesis.
Alkylating agents used in treating neoplasias, such as the nitrogen
mustards, ethylene imines, alkyl sulphonates and antibiotics such
as mitomycin C, suppress cell replication by attacking DNA and
forming covalent alkylate linkages within preformed DNA, thereby
interfering with DNA function and replication. The activity of such
agents is therefore not limited to inhibition of cell replication
alone.
Agents used in treatment of neoplasias such as 8-azaguanidine and
5-fluorouracil inhibit cell replication by being incorporated into
fraudulent RNA. Agents such as actinomycin D, daunorubicin,
nogalomycin, mithramycin and adriamycin are thought to inhibit RNA
polymerase by strongly binding to DNA and thereby inhibiting DNA to
RNA transcription.
Certain agents which inhibit cell replication by arresting
metaphase (examples of such agents are colchicine, vinblastine,
vincristine, podophyllotoxin, and griseofulvin) or arresting
telophase (cytochalasins) have also been shown to be active in
treating neoplasias or microbial infections.
Agents which inhibit cell replication primarily by inhibition of
protein synthesis have found utility in the treatment of microbial
infections. The tetracyclines, streptomycins and neomycin, for
example, inhibit protein synthesis by inhibition of the
mRNA-ribosome-tRNA complex. Chloramphenicol, erythromycin,
lincomycin, puromycin appear to inhibit protein synthesis by
inhibition of the peptidyl synthetase reaction. A miscellaneous
group of antibiotics appear to act by inhibition of translocation
of the ribosome along mRNA. Penicillins act by inhibiting synthesis
of the bacterial cell wall.
Complexes of heavy metals such as platinum have been found to be
active in treatment of certain neoplasias. The inhibition of cell
replication by these complexes is attributed to the in vivo
hydrolysis of one or more of the coordinating ligand sites
occupying positions in the coordination shell of the metal. This
hydrolysis liberates the coordination sites for in vivo interaction
with nucleophilic donor sites which are critical to replication or
survival of the cell population. There is a wide diversity of such
donor sites in vivo, but it is believed that one critical set of
donor sites involves binding of the platinum to two guanine or one
guanine and one adenine residue of opposing strands of DNA.
The mechanisms of action of the various agents employed in treating
protozoan infection are largely unknown. However, it has been
demonstrated that agents which interfere with cell replication can
be active in treating such infections. For example, the
antimalarial agent chloroguanide and the diaminopyrimidines act as
selective inhibitors of plasmodial dihydrofolate reductase thereby
inhibiting plasmodial DNA replication. Tetracyclines possess
antimalarial and antiprotozoal activities possibly acting by
mechanisms similar to those operative in their inhibition of
bacterial replication. The antibiotics puromycin and erythromycin,
as well as tetracyclines which inhibit microbial replication, have
also been employed in treatment of amebiasis. The antiprotozoal
effects of the diamidines is believed to be due to their inhibition
of cell replication by interference with DNA.
Based on what is known from the action of the agents cited above,
one can readily conclude that agents which inhibit cell
replication, regardless of the specific biochemical mechanism
involved, have utility in the treatment of a wide variety of
neoplastic and infectious diseases and in the management of certain
of the body's responses which are mediated through selective in
vivo cell replication.
SUMMARY OF THE INVENTION
The present invention resides in the discovery that a class of
substituted polyaza compounds showing affinity and selectivity for
first transition series elements (atomic numbers 21-30) are capable
of inhibiting cell proliferation of mammalian, bacterial and yeast
(fungal) cell populations and are therefore useful in vitro as
preservatives and in vivo, administered topically or parenterally,
in treatment of a wide variety of conditions including neoplasia,
infection, inflammation, wound care, suppression of the immune
response, inhibition of osteoclasts in treatment of osteoporosis
and in termination of pregnancy. It is believed that the mechanism
for inhibition of cell proliferation by these compounds lies in
their ability to decrease the bioavailability of essential first
transition series elements. The term "decrease the bioavailability"
is used herein to denote a reduction or elimination of the
accessibility of these elements to biological systems and thereby a
reduction or elimination of the ability of these elements to
perform the functions they would otherwise perform in living
systems. Since these compounds decrease the bioavailability of zinc
and iron, they are useful in inhibiting replication of DNA and RNA
viruses. Since these compounds decrease the in vivo availability of
tissue iron, they are also useful in management of free
radical-mediated tissue damage and oxidation-mediated tissue
damage. The compounds can also be prepared as complexes with
radioisotopic or paramagnetic cations of first transition series
elements, or with elements having chemical properties similar to
those of first transition series elements. Complexes prepared in
this manner are useful as diagnostic agents in nuclear medicine and
magnetic resonance imaging.
By virtue of their affinity and selectivity, these substituted
polyaza compounds are effective in treating diseases characterized
by excess of first transition series elements, such as
hemosiderosis (iron) and Wilson's disease (copper).
For therapeutic purposes these agents may be employed in their free
ligand form or in a protected form (for example, as the ester of
the pendant donor group) where the protecting group can be removed
in vivo by enzymatic action to release the active ligand form. The
agents can be administered as either the free chelator, as a
protected form of the chelator, or as physiological salts of these
forms. Physiologically and pharmacologically acceptable salts of
these compounds dissolved in suitable vehicles are fully suitable
for use as pharmaceutical agents.
These compounds of this invention are chemically distinct from
previously known antibiotic and chemotherapeutic agents which
affect cell proliferation and which might also possess some
properties as metal ion ligands. Unlike the chemotherapeutic
complexes between a ligand and a heavy metal cation (such as
platinum, for example) in which the complexed heavy metal provides
the basis for the therapeutic effect and the purpose of the ligand
portion of the complex is related to the in vivo distribution and
hydrolysis rates of the complex, the compounds of this invention
are active in the form of the metal-free ligand and do not require
the addition of a heavy metal to exercise their therapeutic effect.
The compounds of the invention are also chemically distinct from
agents previously employed clinically as chelators of certain first
transition series elements (such as desferrioxamine and
1,2-dimethyl-3-hydroxypyrid-4-one for chelation of iron, and
penicillamine for chelation of copper).
Subclasses of compounds of this invention are novel compounds,
structurally distinct from previously disclosed chelators and any
complexes derived therefrom. Complexes of these subclasses in
combination with radioisotopes or paramagnetic cations are
particularly useful in diagnostic studies in nuclear medicine or in
magnetic resonance imaging, respectively.
DETAILED DESCRIPTION OF THE INVENTION
Abbreviations
Abbreviations are used herein, in conformance with standard
chemical practice, as follows: Bz, benzyl; Me, methyl; Et, ethyl;
Pr, propyl; .sup.i Pr, isopropyl; .sup.i Bu, isobutyl; Bu, butyl;
.sup.t Bu, tertiary-butyl; Ts, para-toluenesulfonyl; Tf.sup.-,
trifluoroacetate; DMSO, dimethylsulfoxide; DMF, dimethylformamide;
DEK, diethyl ketone (3-pentanone); MeOH, methanol; LDA, lithium
diisopropylamide; THF, tetrahydrofuran; Py, pyridine; Ac, acetyl;
Ac.sub.2 O, acetic anhydride
Embodiments of the Invention
The present invention provides methods of in vitro and in vivo
complexing of first transition series element cations. The
invention further provides methods of treating conditions dependent
on the bioavailability of first transition series elements and also
conditions associated with elevated levels of first transition
series elements. Diagnostic methods are also provided which are
useful in nuclear medicine and magnetic resonance imaging. The in
vivo methods involve administering to a patient or host, a
chelating agent (or ligand) which is capable of complexing first
transition series elements as well as elements with chemical
characteristics similar to those of first transition series
elements. For the diagnostic methods, the chelating agent is
administered as a complex of radioisotopic or paramagnetic cations
of first transition series elements (or those with similar
properties).
Among the ligands used in the practice of the present invention are
the embodiments represented by the following formulas: ##STR1##
In Formulas I through IV, R.sup.1, R.sup.2, R.sup.3, and R.sup.4
may be the same or different on any single molecule, and the same
is true for R.sup.11, R.sup.12, and R.sup.13, for R.sup.21,
R.sup.22, and R.sup.23, and for R.sup.31, R.sup.32, and R.sup.33.
Each of these symbols (R.sup.1 through R.sup.33) represents H,
alkyl, alkenyl, aryl, arylalkyl, alkoxy, alkylthio, alkenoxy,
alkenylthio, aryloxy, arylthio, alkyl interrupted by one or more
oxa (--O--), alkenyl interrupted by one or more oxa (--O--), alkyl
interrupted by thia (--S--), alkenyl interrupted by thia (--S--),
aryloxyalkyl, alkoxyaryl, aminoalkyl, aminoalkenyl, aminoaryl,
aminoarylalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxyaryl, or
hydroxyarylalkyl, provided only that these groups do not interfere
with complexation and they are not combined in a manner which
results in a chemically unstable configuration. The alkyl, alkenyl
and aryl groups, or portions of groups, in the foregoing list can
also be substituted with one or more halogen atoms.
In addition to the radicals and radical subclasses listed above,
R.sup.1, R.sup.4, R.sup.11, R.sup.21 and R.sup.31 are further
defined to include: ##STR2##
In Formula V, R.sup.41, R.sup.42, and R.sup.43 may be the same or
different on any single radical, and are defined as H, alkyl,
alkenyl, aryl, arylalkyl, alkoxy, alkylthio, alkenoxy, alkenylthio,
aryloxy, arylthio, alkyl interrupted by oxa (--O--), alkenyl
interrupted by oxa (--O--), alkyl interrupted by thia (--S--),
alkenyl interrupted by thia (--S--), aryloxyalkyl, alkoxyaryl,
aminoalkyl, aminoalkenyl, aminoaryl, aminoarylalkyl, hydroxyalkyl,
hydroxyalkenyl, hydroxyaryl, or hydroxyarylalkyl, provided only
that these groups do not interfere with complexation and that they
are not combined in a manner which results in a chemically unstable
configuration. Here as well, the alkyl, alkenyl and aryl groups, or
portions of groups, in the list can be substituted with one or more
halogen atoms. R.sup.44 in Formula V is defined as H, hydroxy,
amino, alkyl, alkyl interrupted by oxa (--O--), alkoxy, aryl,
aryloxyalkyl, alkoxyaryl, or any of these groups in which the alkyl
and aryl portions are substituted with one or more halogen atoms.
Again, the groups are selected such that they do not interfere with
complexation and are not combined in a manner which results in a
chemically unstable configuration.
The index n is either zero or 1.
The symbol X represents any of the following groups: ##STR3##
In these formulas, R.sup.41, R.sup.42, R.sup.43, and R.sup.44 may
be the same or different on any single radical, and have the same
definitions as R.sup.41, R.sup.42, and R.sup.43 given above.
R.sup.46, R.sup.47, R.sup.48 and R.sup.49 may be the same or
different on any single radical, and are each defined as H, or
alkyl or aryl groups which do not interfere with complexation.
R.sup.46 and R.sup.47 may further be combined as a singie divalent
group, thereby forming a ring structure. R.sup.48 and R.sup.49 are
further defined to include alkoxy, alkyl interrupted by oxa
(--O--), aryloxyalkyl, and alkoxyaryl, combined in a manner which
results in a chemically stable configuration. All alkyl and aryl
groups in this paragraph, including alkyl and aryl portions of
groups, are optionally substituted with one or more halogen
atoms.
R.sup.50, R.sup.51 and R.sup.52 may be the same or different on any
single radical, and are each defined as H, alkyl, alkenyl, aryl,
arylalkyl, alkyloxy, alkylthio, alkenyloxy, alkenylthio, aryloxy,
arylthio, aminoalkyl, aminoalkenyl, aminoaryl, aminoarylalkyl,
hydroxyalkyl, hydroxyalkenyl, hydroxyaryl, or hydroxyarylalkyl.
The index m is an integer which is either 1, 2 or 3.
Returning to Formulas I through IV, further variations within the
scope of this invention are as follows:
(1) Internal cyclizations within these formulas at the nitrogen
atoms, formed by joining together any two of the R.sup.1 and
R.sup.2 groups in Formula I, any two of the R.sup.11 groups in
Formula II, any two of the R.sup.21 groups in Formula IlIl, or any
two of the R.sup.31 groups in Formula IV, as a single divalent
group bridging the two nitrogen atoms, the single divalent group
having the formula ##STR4## in which R.sup.2 and R.sup.3 are as
defined above, and s is at least 2, preferably 2 or 3;
(2) Dimers or other two-molecule combinations of Formulas I through
IV (the molecules being the same or different), formed by bridging
the molecules together through one or more divalent groups of
Formula VI (as defined above) substituted for any one or two of the
R.sup.11 groups in Formula II, any one or two of the R.sup.21
groups in Formula III, or any one or two of the R.sup.31 groups in
Formula IV;
(3) Internal cyclizations at common carbon atoms within these
formulas to form homocyclic rings, by joining one or more of the
R.sup.2, R.sup.12, R.sup.22, or R.sup.32 groups to one or more of
the R.sup.3, R.sup.13, R.sup.23, or R.sup.33 groups at the same
carbon atom, as a single divalent group of Formula VI (as defined
above), and forming one or more such homocyclic rings per structure
in this manner; and
(4) Internal cyclizations involving two carbon atoms separated by a
nitrogen atom within these formulas to form heterocyclic rings, by
joining any two adjacent R.sup.2 groups in Formula I, any two
adjacent R.sup.12 groups in Formula II, any two adjacent R.sup.22
groups in Formula III, or any two adjacent R.sup.32 groups in
Formula IV, as a single divalent group of Formula VI (as defined
above), and forming one or more such heterocyclic rings per
structure in this manner.
In Formula I, the subscripts p and q may be the same or different,
and are each either 2 or 3. The subscript r is 0 to 4 inclusive,
preferably 1 to 2 inclusive.
In Formula II, t, u and v may be the same or different, and are
each either 2 or 3. The value of w is at least 1, more preferably 1
to 4 inclusive, still more preferably 1 to 3 inclusive, and most
preferably either 1 or 2.
The terms used in connection with these formulas have the same
meaning here as they have in the chemical industry among those
skilled in the art. The term "alkyl" thus encompasses both
straight-chain and branched-chain groups and includes both linear
and cyclic groups. The term "alkenyl" refers to unsaturated groups
with one or more double bonds and includes both linear and cyclic
groups. The term "aryl" refers to aromatic groups of one or more
cycles.
For all such groups, those which are useful in the present
invention are those which do not impair or interfere with the
formation of chelate complexes. Within this limitation, however,
the groups may vary widely in size and configuration. Preferred
alkyl groups are those having 1 to 8 carbon atoms, with 1 to 4
carbon atoms more preferred. Prime examples are methyl, ethyl,
isopropyl, n-butyl and tert-butyl. Preferred aryl groups are phenyl
and naphthyl, particularly phenyl. Preferred aryl alkyl groups are
phenylethyl and benzyl, and of these benzyl is the most preferred.
Preferred cycloalkyl groups are those with 4 to 7 carbon atoms in
the cycle, with cycles of 5 or 6 carbon atoms particularly
preferred. Preferred halogen atoms are chlorine and fluorine, with
fluorine particularly preferred.
One particularly preferred subclass of compounds within Formula I
are those in which R.sup.1 is alkyl, alkenyl, aryl, arylalkyl, or
cycloalkyl, substituted at the .beta.-position with hydroxy.
Likewise, R.sup.11 in Formula II, R.sup.21 in Formula III, and
R.sup.31 in Formula IV are each preferably alkyl, alkenyl, aryl,
arylalkyl, or cycloalkyl, substituted at the .beta.-position with
hydroxy. Further preferred are compounds in which one or more, and
preferably two or more, of such groups (R.sup.1, R.sup.11, R.sup.21
and R.sup.31 on the same formula are substituted at the
.beta.-position with hydroxy. Still further preferred are compounds
in which the .beta.-hydroxy substituted groups are further
substituted at the .beta.-position with at least one hydroxymethyl,
alkoxymethyl, alkenoxymethyl, aryloxymethyl, or combinations
thereof, all of which may also be further substituted with halogen.
Included among these are compounds are compounds of Formula III in
which one or more of the R.sup.21 groups are substituted at the
.beta.-position with hydroxy and also with hydroxymethyl,
alkoxymethyl, alkenoxymethyl, or aryloxymethyl, all of which may
also be further substituted with halogen, and the R.sup.22 and
R.sup.23 groups are all hydrogen atoms.
Certain specific groups for R.sup.1, R.sup.11, R.sup.21, and
R.sup.31 are particularly preferred. These are:
2-hydroxy(2,2-diisopropoxymethyl)ethyl and (3-hydroxy-6,
6,7,7-tetramethyl-1,5-dioxacyclohept-3-yl) methyl.
For use in the present inventive methods, the complexes will
preferably have a molecular weight which does not exceed 2000. More
preferably the complexes will have molecular weights of from 200 to
1800, still more preferably of from 400 to 1100.
Among the complexes used in the practice of the present invention
are the embodiments represented by the complexes formed between the
ligands described above and paramagnetic metal cations or
radioisotopic metal cations. These paramagnetic metal cations
include elements of atomic numbers 22 through 29 (inclusive), 42,
44 and 58 through 70 (inclusive). Of these, the ones having atomic
numbers 22 through 29 (inclusive) and 58 through 70 (inclusive) are
preferred, and those having atomic numbers 24 through 29
(inclusive) and 64 through 68 (inclusive) are most preferred.
Examples of such metals are chromium (III), manganese (II), iron
(II), iron (III), cobalt (II), nickel (II), copper (II),
praseodymium (III), neodymium (III), samarium (III), gadolinium
(III), terbium (III), dysprosium (III), holmium (III), erbium (III)
and ytterbium (III). Chromium (III), manganese (II), iron (III) and
gadolinium (III) are particularly preferred, with gadolinium (III)
the most preferred.
Some methods of the present invention will use radioisotopic labels
which will facilitate imaging of various-disease states including
tumors, inflamed joints or lesions or suspected lesions. The use of
gamma emitting radioisotopes is particularly advantageous as they
can easily be counted in a scintillation well counter, do not
require tissue homogenization prior to counting, and can be imaged
with gamma cameras.
Gamma or positron emitting radioisotopes are typically used in
accordance with well known techniques. Suitable gamma-emitting
radioisotopes include .sup.99 Tc, .sup.51 Cr, .sup.59 Fe, .sup.67
Ga, .sup.86 Rb, .sup.111 In and .sup.195 Pt. Suitable
positron-emitters include .sup.68 Ga.
Where indicated, physiologically or pharmacologically compatible
salts of the ligands, or complexes thereof, which have an excess of
acidic groups are formed by neutralizing the acidic moieties of the
ligand with physiologically or pharmacologically compatible cations
from corresponding inorganic and organic bases and amino acids.
Examples are alkali and alkaline earth metal cations, notably
sodium. Further examples are primary, secondary and tertiary
amines, notably, ethanolamine, diethanolamine, morpholine,
glucamine, N,N-dimethylglucamine, and N-methylglucamine (commonly
referred to as "meglumine"). Examples of amino acid cations are
lysines, arginines and ornithines.
Similarly, physiologically and pharmacologically compatible salts
of those ligands which have an excess of basic groups are formed by
neutralizing the basic moieties of the ligand with physiologically
or pharmacologically compatible anions from corresponding inorganic
and organic acids. Examples are halide anions, notably chloride.
Further examples are sulfates, bicarbonate, acetate, pyruvate and
other inorganic and organic acids.
Pharmaceutical compositions comprising the chelates described
herein are prepared and administered according to standard
techniques. The pharmaceutical compositions can be administered
parenterally, i.e., intraarticularly, intravenously,
subcutaneously, or intramuscularly. Suitable formulations for use
in the present invention are found in Remington's Pharmaceutical
Sciences, Mack Publishing Company, Philadelphia, Pa., 17th ed.
(1985).
The chelate compositions can be administered intravenously. Thus,
this invention provides compositions for intravenous administration
which comprise a solution of the chelate suspended in an acceptable
carrier, preferably an aqueous carrier. A variety of aqueous
carriers may be used, e.g., water, buffered water, 0.9% isotonic
saline, and the like. These compositions may be sterilized by
conventional, well known sterilization techniques, or may be
sterile filtered. The resulting aqueous solutions may be packaged
for use as is, or lyophilized, the lyophilized preparation being
combined with a sterile aqueous solution prior to administration.
The compositions may contain pharmaceutically acceptable auxiliary
substances as required to approximate physiological conditions,
such as pH adjusting and buffering agents, tonicity adjusting
agents, wetting agents and the like, for example, sodium acetate,
sodium lactate, sodium chloride, calcium chloride, sorbitan
monolaurate, triethanolamine oleate, etc.
The concentration of chelates, in the pharmaceutical formulations
can vary widely, i.e., from less than about 0.05%, usually at or at
least about 2-5% to as much as 10 to 30% by weight and will be
selected primarily by fluid volumes, viscosities, etc., in
accordance with the particular mode of administration selected. For
diagnosis, the amount of chelates in administered complexes will
depend upon the particular metal cation being used and the
judgement of the clinician. For use in magnetic resonance imaging
the dose typically is between 0.05 to 0.5 millimoles/kg body
weight.
In general, any conventional method for visualizing diagnostic
imaging can be used, depending upon the label used. Usually gamma
and positron emitting radioisotopes are used for imaging in nuclear
medicine and paramagnetic metal cations are used in magnetic
resonance imaging.
The methods of the present invention may be practiced in a variety
of hosts. Preferred hosts include mammalian species, such as
humans, non-human primates, dogs, cats, cattle, horses, sheep, and
the like.
The foregoing description and the following examples are offered
primarily for illustration and not as limitations. It will be
readily apparent to those of ordinary skill in the art that the
operating conditions, materials, procedural steps and other
parameters of the compositions and methods described herein may be
further modified or substituted in various ways without departing
from the spirit and scope of the invention.
EXAMPLES
Example 1
This example illustrates the synthesis of chelators (ligands) which
are useful in the present invention. Section 1.1 illustrates the
synthesis of polyaza bases. Section 1.2 illustrates the synthesis
of alkylating groups. Section 1.3 illustrates the preparation of
chelating agents from alkylation of polyaza bases.
In all examples reactions were carried out in common solvents,
compounds were purified by routine methodology and identity was
established by proton NMR. In some cases identity was further
verified by elemental analysis, mass spectroscopy, C-13 or P-31
NMR, or by synthesis of the identical compound by an independent
alternate synthesis route.
1.1 SYNTHESIS OF POLYAZA BASES
Ethylene diamine (1.1.0), diethylene triamine (1.1.1),
triethylenetetramine (1.1.2), 1,4,7-triazacyclononane (1.1.3),
1,4,7,10-tetraazacyclododecane (1.1.4),
1,4,8,11-tetraazacyclotetradecane (1.1.5) &
1,5,9,13-tetraazacyclohexadecane (1.1.6) and the corresponding
hydrohalide salts were either obtained from commercial sources or
were synthesized employing established methods and were used
directly in the syntheses of chelators (ligands) described in
section 1.3. Additional polyaza bases were synthesized as described
herein. ##STR5## 1.1.7 2,6-Diethyl-1,4,7-triazacyclononane
trihydrobromide
2-(p-toluenesulfonylamino)-1-(p-toluenesulfonyloxy) butane (1.1.8)
and ammonium hydroxide were reacted to form
2-(p-toluenesulfonamino)-1-aminobutane (1.1.9). This was reacted
with 2-(p-toluenesulfonylamino)-1-(p-toluenesulfonyloxy)butane
(1.1.8) and potassium carbonate. The 3,7
bis(p-toluenesulfonylamino)-5-azanonane (1.1.10) product was
purified by chromatography and reacted with p-toluenesulfonyl
chloride to obtain the corresponding tri-p-toluenesulfonyl compound
3,7 bis(p-toluenesulfonylamino)-5-(p-toluenesulfonyl-5-azanonane
(1.1.11). This was purified by chromatography and reacted with 2.2
equivalents of sodium amide in DMF and then with
1,2-di(p-toluenesulfonyloxy)ethane (1.1.12). The
2,6-diethyl-1,4,7-tris(p-toluenesulfonyl) triazacyclononane
(1.1.13) that was obtained following purification was heated in a
solution of HBr in acetic acid to remove the p-toluenesulfonyl
groups and form the titled compound (1.1.7) ##STR6## 1.1.14
1,4,7-Triazabicyclo[7.4.0.sup.8,13 ]tridecane trihydrobromide
1,2-trans-bis(p-toluenesulfonylamino)cyclohexane (1.1.15) was
treated with NaH in DMSO.
1-(p-toluenesulfonylamino)-2-(p-toluenesulfonyl) ethane (1.1.16)
was added to obtain
1-(p-toluenesulfonylamino)-2-[N-p-toluenesulfonyl-N-(2-p-toluenesulfonylam
inoethyl)] aminocyclohexane (1.1.17). This was separated and
reacted with NaH and 1,2-di(p-toluenesulfonyloxy)ethane (1.1.12)
was added. The
2,3-butano-N,N'N"-tris(p-toluenesulfonyl)-1,4,7-triazacyclononane
(1.1.18) obtained was purified by chromatography. The
p-toluenesulfonyl groups were removed by reaction in HBr/Acetic
acid and the 2,3-butano-1,4,7-triazacyclononane trihydrobromide
(1.1.14) product precipitated from solution as the hydrobromide
salt. ##STR7## 1.1.19 1,3-Bis (1,4,7-triazacyclononane) propane
N,N'-bis(p-toluenesulfonyl)-1,4,7-triazacyclononane (1.1.20) was
prepared by reacting (1.1.3) with two equivalents of
p-toluenesulfonyl chloride. Two equivalents of
N,N'-bis(p-toluenesulfonyl)-1,4,7-triazacyclononane (1.1.20)
hydrobromide were reacted with one equivalent of 1,3-diiodopropane
in acetonitrile with excess potassium carbonate.
1,3-Bis[N,N'-bis(p-toluenesulfonyl)-1,4,7-triazacyclononane propane
(1.1.21) was isolated and purified by chromatography. The
p-toluenesulfonyl groups were removed using sulfuric acid and HBr
to yield the title compound (1.1.19). ##STR8## 1.1.22
1,4,7,10-Tetraazabicyclo[5.5.2]tetradecane
1,4,7,10-tetraazadodecane (1.1.4) trihydrobromide in acetonitrile
with potassium carbonate was reacted with glyoxal to form
1,4,7,10-tetraazatetracyclo-[5,5,2,0.sup.4,13,0.sup.10,14 ]
tetradecane (1.1.23). Following separation the pure product was
obtained by low pressure distillation. This was dissolved in
acetonitrile and benzylbromide was added to form
1,7-dibenzylonium-1,4,7,10-tetraazatetracyclo[5,5,2,0.sup.4,13,0.sup.10,14
] tetradecane (1.1.24). Following recrystallization from ethanol
this was reacted with sodium borohydride. HCl was added, followed
by water and NaOH, and the product extracted with chloroform.
Following evaporation of solvent the solids were dissolved in
methanol and HBr was added to obtain
1,7-dibenzyl-1,4,7,10-tetraazabicyclo [5.5.2] tetradecane (1.1.25)
as the hydrobromide salt. This was dissolved in water and reduced
using H.sub.2 and a Pd-C catalyst to remove the benzyl groups.
Purification of the title compound was by crystallization of the
hydrobromide salt. The base form was obtained by low pressure
distillation following addition of base. ##STR9## 1.1.26
1,4,7,10,13-Pentaazabicyclo [8.5.2]heptadecane.
To
1,8-bis(p-toluenesulfonyloxy)-3,6-bis(p-toluenesulfonyl)-3,6-diazaoctane(1
.1.27) was added 1,4,7-triazacyclononane(1.1.3) in acetonitrile
with potassium bicarbonate to obtain 4,7-bis
(p-toluenesulfonyl)-1,4,7,10,1 3-pentaazabicyclo [8.5.2] (1.1.28)
heptadecane. The title compound was purified and the
p-toluenesulfonyl groups were removed by treatment in sulfuric
acid. Purification was done by low pressure distillation. ##STR10##
1.1.29 1,2-Bis(1,4,7-triazabicyclononane-1-yl) ethane.
A mixture of N,N'-bis(p-toluenesulfonyl)-1,4,7-triazabicyclonone
hydrobromide (1.1.13.33), ethylene glycol di-p-toluenesulfonyl or
dibromoethane and excess of potassium carbonate in acetonitrile was
refluxed overnight. The reaction mixture was added to water and
extracted with methylene chloride. The tetratosylated product
(1.1.30) was purified by chromatography. It was suspended in 70%
H.sub.2 SO.sub.4 and heated at 150.degree. C. for 15 hrs. The
reactions cooled to room temperature and then 62% HBr solution was
added. The white precipitate was collected and washed with ethanol.
It was redissolved in water and filtered from tars. The water was
made basic and the title compound (1.1.29) was extracted with
chloroform. ##STR11##
1.2 SYNTHESIS OF ALKYLATING GROUPS FOR ALKYLATION OF POLYAZA BASES
TO FORM CHELATORS DESCRIBED IN EXAMPLE 1.3.
1.2.1 Preparation of Glycidyl Ethers
Glycidyl tosylate (R, S or d,l) (1.2.1.0) was reacted in the
appropriate alcohol solvent employing catalytic amounts of conc.
H.sub.2 SO.sub.4 or equivalent amounts of tetrafluoroboranetherate.
The 1-alkyloxy-2-hydroxy-3-p-toluenesulfonyloxypropane (1.2.1.1)
product was reacted in ether with BuLi to yield the title epoxide.
The following compounds were prepared in this manner.
1.2.1.0 Glycidyl tosylate (R,S or d,l; commercially available).
##STR12##
1.2.1.1 1-Alkyloxy-2-hydroxy-3-p-toluenesulfonyloxypropane.
##STR13##
1.2.1.2 d,l-Glycidyl-isopropyl ether (commercially available).
##STR14##
1.2.1.3 (2R) Glycidyl-isopropyl ether.
1.2.1.4 (2S) Glycidyl-isopropyl ether.
1.2.1.5 d,l-Glycidyl-t-butyl ether. ##STR15##
1.2.1.6 (2R) Glycidyl-t-butyl ether.
1.2.1.7 d,l-Glycidyl allyl ether. ##STR16##
1.2.1.8 d,l-Glycidyl phenyl ether ##STR17## 1.2.2 Preparation of
2,2-Dialkoxymethylene Oxiranes and Spiro-Oxiranes
3-Chloro-2-chloromethyl-1-propane (1.2.2.0) was reacted with the
corresponding sodium alkylate or disodium dialkylate either using
the same alcohol or dialcohol as solvent or using an inert solvent.
The ether product was purified by distillation or chromatography.
Epoxidation was performed using meta-chloroperbenzoic acid in
halogenated solvent. The following compounds were prepared in this
manner.
1.2.2.0 3-Chloro-2-chloromethyl-1-propane (commercially available).
##STR18##
1.2.2.1. 2,2-Bis-ethoxymethyl oxirane. ##STR19##
1.2.2.2 2,2-Bis-methoxymethyl oxirane. ##STR20##
1.2.2.3 2,2-Bis-isopropyloxymethyl oxirane. ##STR21##
1.2.2.4 2,2-Bis-difurfuryloxymethyl oxirane. ##STR22##
1.2.2.5 2, 2-Bis(hydroxymethyl) oxirane
From 2-methylidene-1, 3-dihydroxypropanediol (commercially
available). ##STR23## 1.2.3 Preparation of
Oxiranespiro-3-(1,5-Dioxacycloalkanes).
Various dry glycols in DMF were reacted with NaH and
3-chloromethyl-1-propane (1.2.2.0) was added to the resulting
reaction mixture. Following completion of the reaction the solvents
were removed and the product purified by low pressure distillation.
The purified product in dichloroethane was reacted with
m-chloroperbenzoic acid to form the corresponding epoxide.
Following workup, the epoxide product was purified by distillation.
The following compounds were prepared in this manner.
1.2.3.1 Oxiranespiro-3-(1,5-dioxacycloheptane).
(From ethylene glycol) ##STR24##
1.2.3.2 Oxiranespiro-3-(1,5-dioxa-7,7-dimethylcyclooctane).
(From 2,2-dimethyl propylene glycol) ##STR25##
1.2.3.3 Oxiranespiro-3-(1,5-dioxa-6-methylcycloheptane).
(From 1, 2- dihydroxy propane) ##STR26##
1.2.3.4
Oxiranespiro-3-(1,5-dioxa-6,6,7,7-tetramethylcycloheptane).
[From 2,3-dihydroxy-2,3-dimethyl butane (pinacol)]. ##STR27##
1.2.3.5 Oxiranespiro-3-(benzo [b]-1,5-dioxacycloheptane).
(From 1,2-dihydroxybenzene). ##STR28##
1.2.3.6 Oxiranespiro-3-(1,5-dioxacycloctane).
(From 1,3-propanediol) ##STR29## 1.2.4 Preparation of Miscellaneous
Epoxides
1.2.4.12,2-dimethyl oxirane.
(From 2-methyl-1-propene and m-chloroperbenzoic acid. ##STR30##
1.2.4.2 2-(Isopropyl)-2-[(1-fluoro-1-methyl)ethyl]oxirane.
Reaction between 2,4-dimethyl-3-pentanone (1.2.4.3), trimethylsilyl
chloride, and base gave 2,4-dimethyl-3-trimethysilyloxy-2-pentene
(1.2.4.4) which was reacted with 1-fluoropyridinium triflate
(1.2.4.5) to form 2,4-dimethyl-2-fluoro-3-pentanone (1.2.4.6). This
product was reacted with (CH.sub.3).sub.3 S(O).sup.+ I.sup.- to
form the title compound (1.2.4.2). ##STR31##
1.2.4.7 2,2-Bis-isopropyl oxirane.
(From 2,4-dimethylpentanone using (CH.sub.3).sub.3 S(O).sup.+
I.sup.- as described in 1.2.4.2) ##STR32##
1.2.4.8 2-(1-Fluoroethyl)-2-(1-trimethylsilyloxyethyl) oxirane.
The title compound was obtained in several steps. DEK was
O-silylated using usual procedure. The resulting product was
reacted with 1-fluoropyridinium triflate (1.2.4.5) to yield
2-fluoro-3-pentanone (1.2.4.9). After bromination the
2-bromo-4-fuoro-3-pentanone (1.2.4.10) which was obtained was
reacted with liquid ammonia to form 2-fluoro-4-hydroxy-3-pentanone
(1.2.4.11). The free hydroxyl group was protected with
trimethylsilylchloride to form
2-fluoro-4-trimethylsilyloxo-3-pentanone (1.2.4.12). This product
was reacted with trimethylsulfoxonium iodide to form the title
compound (1.2.4.8). ##STR33##
1.2.4.13 2-(1-Bromoethyl)-3-methyl oxirane.
Bromination of diethyl ketone with bromine gave
2,4-dibromo-3-pentanone (1.2.4.14). This product was reduced with
BH.sub.3 /THF to form 3-hydroxy-2,4-dibromopentane (1.2.4.15).
After treatment with base the title compound (1.2.4.13) was
obtained. ##STR34##
1.2.4.16 2-(1-Fluoroethyl)-3-methyl oxirane.
From reaction between diethylketone and trimethylchlorosilane to
form 3-trimethylsilyloxy-2-pentene (1.2.4.17). This product was
reacted with 1-fluoropyridinium triflate (1.2.4.5) to obtain
2-fluoro-3-pentanone (1.2.4.9). After bromination with pyridinium
bromide followed by reduction using diborane
2-fluoro-4-bromopentane-3-ol (1.2.4.18) was obtained. Reaction of
this product with sodium methylate yielded the title compound
(1.2.4.16). This compound was made also by reacting
2-(1-bromoethyl)-3-methyl oxirane (1.2.4.13) with HF/Py (70%)
followed by treatment of the resulting 2-bromo-4-fluoropentan-3-ol
(1.2.4.18) with K.sub.2 CO.sub.3 /MeOH.
1.2.4.19 2-(1-Fluoroethyl)-2-(1-methoxyethyl) oxirane.
##STR35##
2-(1-Fluoroethyl)-3-methyl oxirane (1.2.4.16) was reacted with
methanol/sulfuric acid to obtain 2-fluoro-4-methoxypentane-3-ol
(1.2.4.20). This product was reacted with chromic
anhydride/pyridine to form 2-fluoro-4-methoxypentane-3-one
(1.2.4.21) which was then reacted with sodium hydride and
trimethylsulfoxonium iodide to obtain the title compound
(1.2.4.19). ##STR36##
1.2.4.22 2-(1-Methoxyethyl)-3-methyl oxirane.
Reaction of 2-(1-Bromoethyl)-3-methyl oxirane (1.2.4.13) with
methanol/sulfuric acid formed 2-bromo-3-hydroxy-4-methoxypentane
(1.2.4.23). This product was reacted with potassium carbonate in
methanol to obtain the title compound (1.2.4.22). ##STR37##
1.2.4.24 2-Ethyl-2-(1-methoxyethyl) oxirane.
Reaction between diethyl ketone and dimethyl hydrazine gave diethyl
ketone-N,N-dimethylhydrazone (1.2.4.25). This product was reacted
with dimethyl disulfide/LDA to obtain
2-methylthio-3-pentanone-N,N-dimethyl hydrazone (1.2.4.26). This
product was reacted with mercuric chloride followed by cupric
chloride to obtain 2-methoxy pentane-3-one (1.2.4.27). Reaction of
the latter compound with sodium hydride/DMSO/trimethylsulfonium
iodide yielded the title compound (1.2.4.24). ##STR38##
1.2.4.28 2-Ethyl-2-(1-trimethylsilyloxyethyl) oxirane.
From reaction between 2-bromo-3-pentanone (1.2.4.29) and hydrazine
obtained 2-hydroxy-3-pentanone (1.2.4.30). This product was reacted
with trimethylchlorosilane/triethylamine to obtain
2-trimethylsilyloxy-3-pentanone (1.2.4.31). This product was
reacted with methylenetriphenyl phosphite and butyllithium to
obtain 2-ethyl-3-trimethylsilyloxy-1-butene (1.2.4.32). After
oxidation with meta-chloroperbenzoic acid in methylene chloride the
title compound (1.2.4.28) was obtained. ##STR39##
1.2.4.33 2,2-Bis(1-fluoroethyl) oxirane.
From reaction between 2-(1-Bromoethyl)-3-methyl oxirane (1.2.4.13)
and HF/pyridine was obtained 2-bromo-4-fluoro-pentane-3-ol
(1.2.4.18). This was reacted with potassium carbonate to obtain
2(1-fluoroethyl)-3-methyl oxirane (1.2.4.16). This was reacted
again with HF/pyridine to obtain 2,4-difluoro-pentane-3-ol
(1.2.4.34). After oxidation with chromium trioxide obtained
2,4-difluoro-3-pentanone (1.2.4.35). The epoxide title compound was
prepared from the ketone as described for 1.2.4.24. ##STR40##
1.2.3.36 2,2-Bis-dichloromethyleneoxirane.
(From direct epoxidation of 3-chloro-2-chloromethyl-1-propene).
##STR41##
1.2.4.37 2,2-Bis(1-methoxyethyl) oxirane.
3-Pentanone was brominated to get 2,4-dibromo-3-pentanone
(1.2.4.11) using conventional methods. The dibromoketone was
reduced with BH.sub.3 *THF to the corresponding alcohol (1.2.4.15).
This compound was reacted with MeONa in methanol to yield
2-(1-bromoethyl)-3-methyl oxirane (1.2.4.13) which after reaction
with MeOH/H.sub.2 SO.sub.4 gave 2-bromo-3-hydroxy-4-methoxy pentane
(1.2.4.38). This intermediate was reacted again with MeONa in
methanol and the resulting 2-(1-methoxyethyl)-3-methyl oxirane
(1.2.4.22) was reacted again with MeOH/H.sub.2 SO.sub.4 to yield
2,4-dimethoxy-3-hydroxy pentane (1.2.4.39). After oxidation with
CrO.sub.3 /Py in methylenechloride the resulting ketone was reacted
with trimethylsulfoxonium iodide to give the title compound
(1.2.4.37). ##STR42## 1.2.5 Phosphite and Alkyl Phosphonate
Esters.
Dialkylphosphites were prepared by reacting diethylphosphite with
the corresponding alcohol.
1.2.5.1 Di-n-butylphosphite, HP(O)[OCH.sub.2 (CH.sub.2).sub.2
CH.sub.3 ].sub.2 (From n-butyl alcohol)
1.2.5.2 Dioctylphosphite, HP(O)[OCH.sub.2 (CH.sub.2).sub.6 CH.sub.3
].sub.2. (From octyl alcohol)
1.2.5.3 Diisobutylphosphite, HP(O)(O.sup.i Bu).sub.2. (From iso
butyl alcohol)
1.2.5.4 Dibenzyl phosphite, HP(O)(OCH.sub.2 Ph).sub.2. (From benzyl
alcohol).
1.2.5.5 Diethyl(2-bromoethyl) phosphonate, BrCH.sub.2 CH.sub.2
P(O)(OEt).sub.2. (From reaction between triethylphosphite and
1,2-dibromethane)
1.2.5.6 Diethyl(2-chloro-1-hydroxyethyl) phosphonate, ClCH.sub.2
CH(OH)P(O)(OEt).sub.2. (From reaction of diethylphosphite and
chloroacetaldehyde).
1.2.5.7 2-(Diethylphosphonate) oxirane. (From 1.2.5.6, sodium
ethoxide). ##STR43## 1.2.6 Halides and Tosylates
1.2.6.1 1-Bromo-2-hydroxy-3,3-dimethylbutane, BrCH.sub.2
CH(OH)G(CH.sub.3).sub.2 (From reduction of bromomethyl-t-butyl
ketone by BH3/THF).
1.2.6.2 1-Bromo-2-t-butyldimethylsilyloxyethane, BrCH.sub.2
CH.sub.2 Si(.sup.t Bu)(CH.sub.3).sub.2 (From bromoethanol and
dimethyl-t-butylsilylchloride)
1.2.6.3
5-(p-Toluenesulfonyloxymethylene)-1-benzyloxy-2-pyrrolidone.
This compound was prepared in several steps. 4-pentenoic acid
(1.2.6.4) was reacted with ethylchloroformate in the usual way to
obtain the active mixed anhydride. To a solution of the mixed
anhydride in chloroform was added triethylamine and
O-benzylhydroxylamine hydrochloride to obtain
O-benzyl-4-pentenohydroxamic acid (1.2.6.5). The double bond was
oxidized using osmium tetroxide/N-methylmorpholine oxide to give
the diol (1.2.6.6). The terminal hydroxyl group was then protected
with t-butyldimethylsilylchloride in the usual way to yield
(1.2.6.7). The secondary hydroxyl group was tosylated using
pyridine/p-toluenesulfonyl chloride. Cyclization of (1.2.6.8) to
the corresponding pyrrolidone (1.2.6.9) was effected by using
sodium carbonate in methanol. The protecting silyl group was
removed by treatment with tetraethylammonium fluoride. The title
compound (1.2.6.3) was prepared by reacting the latter compound
(1.2.6.10) with pyridine/p-toluenesulfonyl chloride in the usual
way. ##STR44##
1.2.6.115-Bromo-1-benzyloxy-2-pyrrolidone.
This compound was prepared in several steps. Butyrolactone was
reacted with PBr3/Br2 to obtain the dibromobutyryibromide
(1.2.6.12). This compound with O-benzyihydroxylamine yielded the
protected dibromohydroxamic acid (1.2.6.13). Cyclization was
effected by base to give the cyclic protected hydroxamic acid
(1.2.6.11). ##STR45## 1.2.7 Preparation of
N-Alkyl-O-Benzylchloroacetohydroxamic Acids.
This class of compounds was prepared from chloroacetyl chloride and
the suitable N-Alkylhydroxylamine followed by O-benzylation with
benzyl bromide. In certain instances the O-benzyl
alkylhydroxylamine was used as the starting material. O-Methyl
chloroacetoxyhydroxamic acid was prepared employing
O-methylhydroxylamine as starting material.
1.2.7.1 O-Benzyl-N-Methyl Chloroacetohydroxamic acid, ClCH.sub.2
CON(Me)(OBz).
1.2.7.2 O-Benzyl-N-isopropyl-Chloroacetohydroxamic acid, ClCH.sub.2
CON(.sup.i Pr)(OBz).
1.2.7.3 O-Benzyl-N-tert-butyl-Chloroacetohydroxamic acid,
ClCH.sub.2 CON(.sup.t Bu)(OBz).
1.2.7.4 O-Benzyl Chloroacetohydroxamic acid, ClCH.sub.2
CONH(OBz)
1.2.7.5 O-Methyl chloroacetohydroxamic acid, ClCH.sub.2
CONH(OMe)
1.3 SYNTHESIS OF CHELATORS (LIGANDS)
1.3.1 Synthesis of Polyaza Ligands with Pendant Arms Containing
.beta.-Hydroxy Groups and Their Derivatives.
This family of compounds was prepared by reacting polyaza free
bases with epoxides or halohydrines in water or alcohol
solvents.
1.3.1.1 N,N',N"-Tris
(2-hydroxy-3-isopropoxypropyl)-1,4,7-Triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3) and d,I-glycidyl isopropyl
ether (1.2.1.2). ##STR46##
1.3.1.2 (R,R,R)
N,N',N"-Tris(2-hydroxy-3-isopropoxypropyl)-1,4,7-triazacyclononane.
From 1,4,7-Triazacyclononane (1.1.3) and (2R) glycidyl isopropyl
ether (1.2.1.3). ##STR47##
1.3.1.3 (S,S,S)
N,N',N"-Tris(2-hydroxy-3-isopropoxypropyl)-1,4,7-triazacyclononane.
From 1,4,7-Triazacyclononane and (2S) glycidyl isopropyl ether
(1.2.1.4). ##STR48##
1.3.1.4
N,N',N"-Tris(2-hydroxy-3-t-butoxypropyl)-1,4,7-triazacyclononane.
From 1,4,7-Triazacyclononane (1.13) and (d,l) glycidyl-t-Butyl
ether (1.2.1.5). ##STR49##
1.3.1.5 (R,R,R)
N,N',N"-Tris(2-hydroxy-3-t-butoxypropyl)-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3) and (R) glycidyl t-Butyl ether
(1.2.1.6). ##STR50##
1.3.1.6 N,N',N"-Tris(2-hydroxy-3
methoxypropyl)-1,4,7-triazacyclononane
From 1,4,7-Triazacyclononane (1.1.3) and (d,l) glycidyl methyl
ether (commercially available). ##STR51##
1.3.1.7 N,N',N"-Tris(2,3-dihydroxy propyl)-1,4,7-
triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3) and
1-bromo-2,3-dihydroxypropane (commercially available) and excess of
potassium carbonate or 1-chloro-2,3-dihydroxypropane (commercially
available) and base. ##STR52##
1.3.1.8
N,N',N"-Tris(1-methoxy-2-hydroxy-2-methylpropyl)-1,4,7-triazacyclononane.
From 1,4,7-Triazacyclononane (1.1.3) and (d,l)
3,3-Dimethyl-2-methoxy oxirane (1-methoxy-2-methylpropylene,
commercially available). ##STR53##
1.3.1.9
N,N',N"-Tris(2-hydroxy-3-allyloxypropyl)-1,4,7-triazacyclononane.
From 1,4,7-Triazacyclononane (1.1.3) and (d,l) glycidyl allyl ether
(1.2.1.7). ##STR54##
1.3.1.10
N,N',N"-Tris(2-hydroxy-3-phenoxypropyl)-1,4,7-triazacyclononane.
From 1,4,7-Triazacyclononane (1.1.3) and (d,l) glycidyl phenyl
ether (1.2.1.8). ##STR55##
1.3.1.11
N,N',N"-Tris(2-hydroxy-2,2-diethoxymethylene)ethyl-1,4,7-triazacyclononane
.
From 1,4,7-triazacyclononane (1.1.3) and 2,2-Bis-ethoxymethyl
oxirane(1.2.2.1). ##STR56##
1.3.1.12
N,N',N"-Tris(2-hydroxy-2,2-dimethoxymethyl)ethyl-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3) and 2,2-Bis-methoxyoxymethyl
oxirane (1.2.2.2). ##STR57##
1.3.1.13
N,N',N"-Tri(2-hydroxy-(2,2-diisopropyloxymethyl)ethyl-1,4,7-triazacyclonon
ane.
From 1,4,7-triazacyclononane (1.1.3) and 2,2-Bis-Isopropoxymethyl
oxirane (1.2.2.3). ##STR58##
1.3.1.14
N,N',N"-Tris[2-hydroxy-bis(2-furfuryloxymethyl)ethyl]-1,4,7-triazacyclonon
ane.
From 1,4,7-triazacyclononane (1.1.3) and 2,2-Bis(furfuryloxymethyl)
oxirane (1.2.2.4). ##STR59##
1.3.1.15
N,N',N"-Tris(3-hydroxy-1,5-dioxacycloheptyl-3-methyl)-1,4,7-triazacyclonon
ane.
From 1,4,7-Triazacyclononane (1.1.3) and
oxiranespiro-3-(1,5-dioxacycloheptane) (1.2.3.1). ##STR60##
1.3.1.16 N,N',
N"-Tris[(3-Hydroxy-7,7-dimethyl-1,5-dioxacyclooct-3-yl)-methyl]-1,4,7-tria
zacyclononane.
From 1,4,7-Triazacyclononane (1.1.3) and
oxiranespiro-3-(1,5-dioxa-7,7-dimethylcyclooctane) (1.2.3.2).
##STR61##
1.3.1.17 N,
N',N"-Tris[(3-hydroxy-7-methyl-1,5-dioxacyclohept-3-yl)methyl]-1,4,7-triaz
acyclononane.
From 1,4,7-Triazacyclononane (1.1.3) and
Oxiranespiro-3-(1,5-dioxa-6-methylcycloheptane(1.2.3.3).
##STR62##
1.3.1.18
N,N',N"-Tris[(3-hydroxy-6,6,7,7-tetramethyl-1,5-dioxacyclohept-3-yl)methyl
]-1,4,7-Triazacyclononane.
From 1,4,7-Triazacyclononane (1.1.3) and
oxiranespiro-3-(1,5-dioxa-6,6,7,7-tetramethylcycloheptane)
(1.2.3.4). ##STR63##
1.3.1.19
N,N',N"-Tris[(3-hydroxy-benzo[b]-1,5-dioxacycloheptyl)methyl]1,4,7-triazac
yclononane.
From 1,4,7-triazacyclononane (1.1.3) and
oxiranespiro-3-(benzo[b]-1,5-dioxacycloheptane) (1.2.3.5).
##STR64##
1.3.1.20
N,N',N"-Tris[(3-hydroxy-1,5-dioxacyclooctane-3-yl)methyl]-1,4,7-triazacycl
ononane.
From 1,4,7-triazacyclononane (1.1.3) and
oxiranespiro-3-(1,5-dioxacyclooctane) (1.2.3.6). ##STR65##
1.3.1.21
N,N',N"-Tris(2-hydroxy-2-methylpropyl)-1,4,7-Triazacyclononane.
From 1,4,7-Triazacyclononane (1.1.3) and 2,2-Dimethyl oxirane
(1.2.4.1) ##STR66##
1.3.1.22 N,N',N"-Tris [(4-fluoro-2-hydroxy-3-i-propyl-4-methyl)
pentyl]-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3) and
2-isopropyl-2-(1-fluoro-1-methylethyl) oxirane (1.2.4.2).
##STR67##
1.3.1.23
N,N',N"-Tris-[2-hydroxy-3-(1-fluoroethyl)-4-hydroxypentyl]-1,4,7-triazacyc
lononane.
From 1,4,7-triazacyclononane (1.1.3) and
2-(1-trimethylsilyloxyethyl)-2-(1-fluoroethyl) oxirane (1.2.4.8).
##STR68##
1.3.1.24 N,N',N"-Tris
[2-hydroxy-2-(1-fluoroethyl)-2-(1-methoxyethyl)ethyl]-1,4,7-triazacyclonon
ane.
From 1,4,7-triazacyclononane (1.1.3) and
2-(1-Fluoroethyl)-2-(1-methoxyethyl) oxirane (1.2.4.19).
##STR69##
1.3.1.25 N,N',N"-Tris(2-hydroxy-2-ethyl-3-methoxy
butyl)-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3) and 2-ethyl-2-(1-methoxyethyl)
oxirane (1.2.4.24). ##STR70##
1.3.1.26
N,N',N"-Tris(2,3-dihydroxy-2-ethyl)butyl]-1,4,7-Triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3) and
2-ethyl-2-(1-trimethylsilyloxyethyl) oxirane (1.2.4.28).
##STR71##
1.3.1.27 N,N',N"-Tris[2-hydroxy-2,2-bis(1-fluoro ethyl)
ethyl]-1,4,7-triazacyclononane.
From 1,4,7-triazacylononane (1.1.3) and 2,2-bis(1-fluoroethyl)
oxirane (1.2.4.33): ##STR72##
1.3.1.28 N,N',N"-Tris[2-hydroxy-2,2-bis(1-methoxyethyl)
ethyl]-1,4,7-triazacyclononane.
From 1,4,7-Triazacyclononane (1.1.3) and
2,2-(1-methoxyethyl)oxirane (1.2.4.37). ##STR73##
1.3.1.29
N,N',N"-Tris[(3,3-dimethyl-2-hydroxy)butyl]-1,4,7-triazacyclononane.
From 1,4,7-Triazacyclononane (1.1.3),
1-Bromo-2-hydroxy-3,3-dimethylbutane (1.2.6.1) and sodium
carbonate. ##STR74##
1.3.1.30 N,N',N"-Tris(2-hydroxypropyl)-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3) and propylene oxide.
##STR75##
1.3.1.31
N,N',N"-Tris(2,2-dimethoxyethanyl)-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3), 1-chloro-2,2-dimethoxyethane
(commercially available) and sodium carbonate. ##STR76##
1.3.1.32
N,N',N"-Tris(2-hydroxycyclopentan-1-yl)-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3), 1,2-epoxycyclopentane
(commercially available) and sodium carbonate. ##STR77##
1.3.1.33
N,N',N"-Tris(2-hydroxycyclohexane-1-yl)-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3), 1,2-epoxycyclohexane
(commercially available) and sodium carbonate. ##STR78##
1.3.1.34 N,N',N"-Triallyl-1,4,7-Triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3), sodium hydride and allyl
bromide. ##STR79##
1.3.1.35
N,N',N"-Tris[(3-chloro-2-hydroxy)propyl)]-1,4,7-Triazacyclononane.
From N,N',N"-triallyl-1,4,7-triazacyclononane(1.3.1.34) and aqueous
chlorine. ##STR80##
1.3.1.36
1,2-Bis-(N,N'-di-2-hydroxyethyl-1,4,7-triazacyclononane-1-yl)
ethane.
From 1,2-bis-(1,4,7-triazacyclononane-1-yl) ethane polyhydrobromide
and ethylene oxide. ##STR81##
1.3.1.37
N,N',N",N"'-Tetrakis-(2-hydroxyethyl)-1,4,7,10-tetraazacyclododecane.
From 1,4,7,10-Tetraazacyclododecane (1.1.4) and bromoethanol.
##STR82##
1.3.1.38
N,N',N",N"'-Tetrakis(2,3-dihydroxypropyl)-1,4,7,10-tetraazacyclotetradecan
e.
From 1,4,7,10-tetraazacyclotetradecane (1.1.4),
1-chloro-2,3-propanediol (commercially available) and base.
##STR83##
1.3.1.39 4,10-Bis(2-Hydroxypropyl)-1,4,7,10-tetraazabicyclo [5.5.2]
tetradecane.
From 1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (1.1.4) and
propylene oxide. ##STR84##
1.3.1.40
4,10-Bis-(2-hydroxyethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane.
From
4,10-Bis(dimethoxycarbonylmethyl)-1,4,7,10-tetraazabicyclo[5.5.2]
tetradecane (1.3.6.8) and lithium aluminum hydride. ##STR85##
1.3.1.41
4,10-Bis[(2-Hydroxy-2-phenyl)ethyl]-1,4,7,10-tetraazabicyclo[5.5.2]tetrade
cane.
From 1,4,7,10-Tetraazabicyclo[5.5.2]tetradecane (1.1.4) and styrene
oxide. ##STR86##
1.3.1.42 4,10-Bis-(2,3-dihydroxypropyl)-1,4,7,10-tetraazabicyclo
[5.5.2] tetradecane.
From 1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (1.1.4) and
glycidol. ##STR87##
1.3.1.43
N,N',N",N"'-Tetrakis-(2,3-dihydroxypropyl)-1,4,8,11-tetraazacyclohexadecan
e.
From cyclam (1.1.5) and glycidol. ##STR88##
1.3.1.44 cis, trans
N,N,N',N'-Tetrakis(2,3-dihydroxypropyl)-1,2-diamino-cyclohexane.
From cis,trans 1,2-diaminocyclohexane (commercially available) and
glycidol. ##STR89##
1.3.1.45 trans
N,N,N',N'-Tetrakis(2,3-dihydroxypropyl)-1,2-diamino-cyclohexane.
From trans-1,2-diaminocyclohexane (commercially available) and
glycidol. ##STR90##
1.3.1.46
N,N,N',N'-Tetrakis(2,3-dihydroxypropyl)-ethylenediamine.
From ethylenediamine (1.1.0) and glycidol. ##STR91##
1.3.1.47
N,N,N',N",N"'-Pentakis(2,3-dihydroxypropyl)-diethylenetriamine.
From diethylenetriamine (1.1.1), 1-chloro-2,3-propanediol and base.
##STR92##
1.3.1.48 N,N,N',N",N"',N"'-Hexaakis(2,3-dihydroxypropyl)
triethylenetetramine.
From triethylenetetramine (1.1.2) and glycidol. ##STR93##
1.3.1.49
N,N,N',N'-Tetrakis(2,3-dihydroxypropyl)-1,2-diamino-2-methylpropane.
From 1,2-diaminomethylpropane and glycidol. ##STR94##
1.3.1.50
N,N,N',N'-Tetrakis(2,3-dihydroxypropyl)-1,2-diaminopropane.
From 1,2-diaminopropane and glycidol. ##STR95##
1.3.1.51
N,N',N"-Tris(2,3-diacetoxypropyl)-1,4,7-triazacyclononane.
From 1.3.1.7 and Py/Ac.sub.2 O. ##STR96##
1.3.1.52 N,N',N"-tris(Dimethyl-2,3-isopropylidene
propyl)-1,4,7-triazacyclononane.
From 1.3.1.7 and 2,2-dimethoxypropane/p-toluenesulfonic acid.
##STR97##
1.3.1.53 4,10-(2-Diacetoxyoxypropyl)-1,4,7,10-tetraazabicyclo
[5.5.2] tetradecane.
From 1.3.1.39 and Py/Ac.sub.2 O. ##STR98##
1.3.1.54
N,N',N"-Tris[(2,4-dihydroxy-3-isopropyl-4-methyl)pentyl]-1,4,7-triazacyclo
nonane.
From 1,4,7-triazacyclononane (1.1.3) and 2,2-bis(hydroxymethyl)
oxirane. ##STR99##
1.3.1.55 N,N',N"-Tris-[2-hydroxy-(2,2-dihydroxymethyl)ethyl]
-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3) and 2,2-bis(hydroxymethyl)
oxirane (1.2.2.5). ##STR100## 1.3.2 Synthesis of Polyaza Ligands
With Alkylphosphonate Mono- and Di-Esters Pendant Arms.
1.3.2.1 Preparation
Chelators which have three identical methylene phosphonate diester
arms were prepared by reacting the trihydrobromide polyaza bases
with formaldehyde and dialkylphosphite. The hexa-ester was
hydrolized to the tri-ester by heating with NaOH dissolved in the
appropriate alcohol (the same R group as in the dialkylphosphite).
In some cases products were obtained by reacting the amine base
with haloalkylphosphonates or epoxyphosphonates.
1.3.2.1
N,N',N"-Tris(dibutylphosphorylmethyl)-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3) trihydrobromide, formaldehyde
solution and di-n-butyl phosphite (1.2.5.1). ##STR101##
1.3.2.2 N,N',N"-Tris(dihydroxyphosphorylmethylmono butyl
ester)-1,4,7-triazacyclononane.
From N,N',N"-tris(dibutylphosphorylmethyl)-1,4,7-triazacyclononane
(1.3.2.1) and KOH/butanol. ##STR102##
1.3.2.3
N,N',N"-Tris(diethylphosphorylmethyl)-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3) trihydrobromide, formaldehyde
solution and diethyl phosphite (commercially available).
##STR103##
1.3.2.4 N,N',N"-Tris(dihydroxyphosphorylmethyl monoethyl
ester)-1,4,7-triazacyclononane.
From N,N',N"-tris(diethylphosphorylmethyl)-1,4,7-triazacyclononane
(1.3.2.3) and NaOH/EtOH. ##STR104##
1.3.2.5
N,N',N"-Tris(dioctylphosphorylmethyl)-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3), formaldehyde and
dioctylphosphite (1.2.5.2). ##STR105##
1.3.2.6 N,N',N"-Tris(dihydroxyphosphorylmethyl monooctyl
ester)-1,4,7-triazacyclononane.
From 1.3.2.5 and NaOH in octyl alcohol. ##STR106##
1.3.2.7
N,N',N"-Tris(diisobutylphosphorylmethyl)-1,4,7-triazacyclononane.
From 1,4,7-Triazacyclononane (1.1.3), formaldehyde and
diisobutylphosphite (1.2.5.3). ##STR107##
1.3.2.8 N,N',N"-Tris(dihydroxyphosphorylmethyl monoisobutyl
ester)-1,4,7-triazacyclononane.
From 1.3.2.7 and NaOH in isobutyl alcohol. ##STR108##
1.3.2.9
N,N',N"-Tris(dibenzylphosphorylmethyl)-1,4,7-triazacyclononane.
From 1,4,7-Triazacyclononane (1.1.3), formaldehyde and
dibenzylphosphite (1.2.5.4). ##STR109##
1.3.2.10
N,N',N"-Tris(diethylphosphorylethyl)-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3) trihydrobromide, potassium
carbonate and diethyl(2-bromoethyl)phosphonate (1.2.5.5).
##STR110##
1.3.2.11
N,N',N",N"'-Tetrakis(diethylphosphorylmethyl)-1,4,7,10-Tetraazacyclodecane
.
From 1,4,7,10-Tetraazacyclodecane (1.1.4) trihydrobromide,
formaldehyde and diethylphosphite (commercially available).
##STR111##
1.3.2.12
N,N',N",N"'-Tetrakis(diethylphosphorylethyl)-1,4,7,10-tetraazacyclododecan
e.
From 1,4,7,10-tetraazacyclododecane (1.1.4) trihydrobromide,
potassium carbonate and diethyl(2-bromoethyl)phosphonate (1.2.5.5).
##STR112##
1.3.2.13 4,10-Bis(diethylyphosphorylethyl)-1,4,7,10-tetraazabicyclo
[5.5.2] tetradecane.
From 1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (1.1.20)
dihydrobromide, potassium carbonate and
diethyl(2-bromoethyl)phosphonate (1.2.5.5). ##STR113##
1.3.2.14 4,10-Bis(diethylphosphoryl
methyl)-1,4,7,10-tetraazabicyclo [5.5.2] tetradecane.
From 1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (1.1.20)
trihydrobromide, formaldehyde and diethylphosphite (commercially
available). ##STR114##
1.3.2.15
N,N',N"-Tris(diethylphosphorylmethyl)-1,4,7,10,13-pentaazabicyclo
[8.5.2]heptadecane.
From 1,4,7,10,13-pentaazabicyclo[8.5.2]heptadecane (1.1.25),
formaldehyde and diethylphosphite (commercially available).
##STR115##
1.3.3 Synthesis of Polyaza Ligands with Identical Alkylphosphonic
Acid Pendant Arms.
These compounds were prepared by either hydrolizing the ester
groups of the compounds described under 1.3.2, or from the polyaza
base, formaldehyde and phosphorous acid.
1.3.3.1
1,2-Bis(N,N'-bis(dihydroxyphosphrylmethyl)-1,4,7-triazacyclononan-1-yl)
ethane.
From 1,2-bis-(1,4,7-triazacyclononan-1-yl)ethane (11.28),
formaldehyde and phosphorous acid. ##STR116##
1.3.3.2
1,2-Bis(N,N'-bis(dihydroxyphosphorylmethyl)-1,4,7-triazacyclononan-1-yl)pr
opane.
From 1,2-Bis-(1,4,7-triazacyclononan-1-yl)propane (1.1.1 9),
formaldehyde and phosphorous acid. ##STR117##
1.3.3.3
4,10-Bis(dihydroxyphosphorylmethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetrade
cane.
From 1,4,7,10-Tetraazabicyclo[5.5.2]tetradecane (1.1.20)
trihydrobromide, formaldehyde and phosphorous acid. ##STR118##
1.3.3.4
4,7,13-Tris(dihydroxyphosphorylmethyl)-1,4,7,10,13-pentaazabicyclo[8.5.2]h
eptadecane.
From hydrolysis of
1,4,7,13-tris(diethylphosphorylmethyl)-1,4,7,10,13-pentaazabicyclo[8.5.2]h
eptadecane (1.3.2.15) by HCl. ##STR119##
The following compounds were prepared from the corresponding
diesters by hydrolysis with HCl.
1.3.3.5
N,N',N"-Tris(dihydroxyphosphorylethyl)-1,4,7-triazacyclononane.
##STR120##
1.3.3.6
N,N',N",N"'-Tetrakis(dihydroxyphosphorylethyl)-1,4,7,10-tetraazacyclododec
ane. ##STR121##
1.3.3.7
4,10-Bis(dihydroxyphosphorylethyl)-1,4,7,10-tetraazabicyclo[5.5.2]
tetradecane. ##STR122## 1.3.4 Synthesis of Polyaza Ligands with
Pendant Arms Containing
Phosphonate Esters and Acids with Alpha Substituent Groups.
Alkyl or aryl groups a to the phosphonate moiety were prepared by
alkylation of the corresponding ligand in the form of its
dialkylphosphonate.
1.3.4.1
N,N',N"-Tris[.alpha.-dihydroxyphosporyl-.alpha.-benzyl)methyl]-1,4,7-Triaz
acyclononane.
From
N,N',N"-Tris[(.alpha.-diethylphosporyl-.alpha.-benzyl)methyl]-1,4,7-triaza
cyclononane (U.S. Pat. No. 5,380,515) and trimethylsilyl iodide.
##STR123##
1.3.4.2
N,N',N"-Tris{[(diethylphosphoryl)-.alpha.-hydroxy]ethyl}-1,4,7-triazacyclo
nonane.
From 1,4,7-triazacyclononane (1.1.3) and 2-diethylphosphoryl
oxirane (1.2.5.7). ##STR124##
1.3.4.3
N,N',N'-Tris[dihydroxyphosphoryl-.alpha.-hydroxy)ethyl]-1,4,7-triazacyclon
onane.
From 1.3.4.2 and HCl. ##STR125## 1.3.5 Synthesis of Polyaza Ligands
with Pendant Arms Containing Hydroxamate Groups.
These compounds were prepared by reacting 1,4,7-tetraazacyclononane
(1.1.3) trihydrobromide with a N-alkyl-O-benzyl
chloroacetohydroxamic acid in the presence of a base. The free
hydroxamic acid was obtained by removing the benzyl protecting
group by hydrogenolysis.
1.3.5.1
N,N',N"-Tris[(N-methyl-N-benzyloxycarbamoyl)methyl]1,4,7-triazacyclononane
.
From 1,4,7-triazacyclononane, sodium carbonate and
O-benzyl-N-methyl chloroacetohydroxamate (1.2.7.1). ##STR126##
1.3.5.2
N,N',N"-Tris[(N-methyl-N-hydroxycarbamoyl)methyl]-1,4,7-triazacyclononane.
From
N,N',N"-Tris[(N-methyl-N-benzyloxycarbamoyl)methyl]-1,4,7-triazacyclononan
e (1.3.5.1) and H.sub.2 and Pd/C. ##STR127##
1.3.5.3
N,N',N"-Tris[(N-isopropyl-N-benzyloxycarbamoyl)methyl]-1,4,7-triazacyclono
nane.
From 1,4,7-Triazacyclononane trihydrobromide and
chloroaceto-N-isopropyl-O-benzyl hydroxamate (1.2.7.2).
##STR128##
1.3.5.4
N,N',N"-Tris[(N-isopropyl-N-hydroxycarbamoyl)methyl]-1,4,7-triazacyclonona
ne.
From 1.3.5.3 and H.sub.2 and Pd/C. ##STR129##
1.3.5.5
N,N',N"-Tris[(N-t-butyl-N-benzyloxycarbamoyl)methyl]-1,4,7-triazacyclonona
ne.
From 1,4,7-triazacyclononane trihydrobromide and
chloroaceto-N-t-butyl-O-benzyl hydroxamate (1.2.7.3).
##STR130##
1.3.5.6
N,N',N"-Tris[(N-t-butyl-N-hydroxycarbamoyl)methyl]-1,4,7-triazacyclononane
.
From 1.3.5.5, H.sub.2 and Pd/C. ##STR131##
1.3.5.7
N,N',N"-Tris[(N-benzyloxycarbamoyl)methyl]-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3) trihydrobromide and
chloroaceto-O-benzyl hydroxamate (1.2.7.4). ##STR132##
1.3.5.8
N,N',N"-Tris[(N-hydroxycarbamoyl)methyl]-1,4,7-triazacyclononane.
From 1.3.5.7 and H.sub.2 and Pd/C. ##STR133##
1.3.5.9
N,N',N"-Tris[(N-methoxycarbamoyl)methyl]-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3) trihydrobromide and
chloroaceto-O-methyl hydroxamate (1.2.7.5). ##STR134##
1.3.5.10
4,10-Bis[(N-benzyloxycarbamoyl-N-methyl)methyl]-1,4,7,10-tetraazabicyclo[5
. 5. 2]tetradecane.
From 1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (1.1.20)
dihydrobromic acid, sodium carbonate and chloroaceto-O-benzyl
hydroxamate (1.2.7.4). ##STR135##
1.3.5.11
4,10-Bis[(N-hydroxycarbamoyl-N-methyl)methyl]-1,4,7,10-Tetraazabicyclo
[5.5.2] tetradecane.
From 1.3.5.10 and H.sub.2 and Pd/C. ##STR136##
1.3.5.12
N,N',N"-Tris[(1-benzyloxy-2-pyrrolidone-5-yl)methyl]-1,4,7-triazacyclonona
ne.
From 1,4,7-triazacyclononane (1.1.3),
5-(p-toluenesulfonyloxymethyl)-1-benzyloxy-2-pyrrolidone (1.2.6.3)
and base. ##STR137##
1.3.5.13
N,N',N"-Tris[(1-oxy-2-pyrrolidone-5-yl)methyl]-1,4,7-triazacyclononane.
From 1.3.5.12 and Pd/C (5%) and H.sub.2. ##STR138##
1.3.5.14
N,N',N"-Tris(1-benzyloxy-2-pyrrolidone-5-yl)-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3),
5-bromo-1-benzyloxy-2-pyrrolidone (1.2.6.11) and base.
##STR139##
1.3.5.15
N,N',N"-Tris(1-oxy-2-pyrrolidone-5-yl)-1,4,7-triazacyclononane.
From 1.3.5.14 and Pd/C (5%) and H.sub.2. ##STR140## 1.3.6 Synthesis
of Polyaza Ligands with Pendant Arms Containing Carboxyl Groups And
The Corresponding Esters.
Compounds were prepared by reacting polyaza bases with either halo
carboxylic acids or by reductive alkylation with aldo or keto
acids. The esters were prepared either by reacting directly with
halo carboxylic acid esters or by reaction of the free acid with
SOCl2/alcohol.
1.3.6.1 N,N',N"-Tris(carboxymethyl)-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3), glyoxylic acid and H.sub.2
/Pt. ##STR141##
1.3.6.2
N,N',N"-Tris(methoxycarbonylmethyl-1,4,7-triazacyclononane.
From N,N', N"-tris(carboxymethyl)-1,4,7-triazacyclononane in
methanol and SOCl.sub.2. ##STR142##
1.3.6.3 N,N',N"-Tris(.alpha.-methylcarboxymethyl
)-1,4,7-Triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3), pyruvic acid and H.sub.2 /Pt.
##STR143##
1.3.6.4
N,N',N"-Tris(methoxycarbonylmethyl-1,4,7-triazabicyclo-[7.4.0.sup.8,13
]tridecane.
From 1,4,7-Triazabicyclo[7.4.0.sup.8,13 ]tridecane hydrobromide
(1.1.14), glyoxylic acid and H.sub.2 /PtO.sub.2 in methanol.
##STR144##
1.3.6.5
N-(.alpha.-methylcarboxymethyl)-1,4,7-triazabicyclo[7.4.0]tridecane.
From 1,4,7-triazabicyclo[7.4.0.sup.8,13 ]tridecane (1.1.14),
pyruvic acid and H.sub.2 /PtO.sub.2. ##STR145##
1.3.6.6 N,N',N"-Tris(ethoxycarbonylmethyl)-1,4,7-triazacyclo
[7.4.0]tridecane.
From 1,4,7-triazabicyclo[7.4.0.sup.8,13 ]tridecane (1.1.14), sodium
methoxide and ethyl bromoacetate. ##STR146##
1.3.6.7
1,2-Bis-(4,7-carboxymethyl-1,4,7-triazacyclononan-1-yl)ethane.
From 1,2-Bis(1,4,7-triazacyclononan-1-yl)ethane (1.1.28),
chloroacetic acid and NaOH. ##STR147##
1.3.6.8
4,7-Bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane.
From 1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (1.1.22),
chloroacetic acid and NaOH. ##STR148##
1.3.6.9
4,7-Bis(methoxycarboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]
tetradecane.
From 4,7-bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]
tetradecane (1.1.20) in MeOH/H.sub.2 SO.sub.4. ##STR149##
1.3.6.10 N,N',N"-Tris(carboxyethyl)-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3), 3-chloropropionic acid and
base. ##STR150##
1.3.6.11
4,10-Bis(ethoxycarboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]
tetradecane.
From 1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (1.1.20) and ethyl
acrylate. ##STR151##
1.3.6.12
4,10-Bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane.
From 1.3.6.11 by acid hydrolysis. ##STR152##
1.3.6.13
N,N',N"-Tris(ethoxycarbonylmethyl)-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3), ethyl bromoacetate and base.
##STR153##
1.3.6.14
1,2-Bis-(4,7-methoxycarbonylmethyl-1,4,7-triazacyclononan-1-yl)-ethane.
From 1,2-bis-(4,7-carboxymethyl-1,4,7-Triazacyclononan-1-yl)ethane
(1.3.6.7), MeOH/SOCl.sub.2. ##STR154## 1.3.7 Synthesis of Polyaza
Ligands with Pendant Arms Containing Aldehyde or Ketone Groups.
1.3.7.1
N,N',N"-Tris(2,2-dimethoxyethyl)-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3), 1-chloro-2,2-dimethoxyethane
(commercially available) and sodium carbonate. ##STR155##
1.3.7.2
N,N',N"-Tris-(3,3-dimethyl-2-oxo-butyl)-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3), bromomethyl t-butyl ketone
(commercially available) and sodium carbonate. ##STR156## 1.3.8
Synthesis of Polyaza Ligands with Pendant Arms Containing Pyrrole
Groups.
1.3.8.1
N,N',N"-Tris(-pyrrol-2-yl-methyl)-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3), pyrrole-2-carboxaldehyde
(commercially available) and H.sub.2 /PtO.sub.2. ##STR157## 1.3.9
Synthesis of Polyaza Ligands with Pendant Arms Containing Amine
Groups.
1.3.9.1
N,N',N"-Tris(2-p-toluenesulfonyloxyethyl)-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3),
2-(p-toluenesulfonylamino)-1-(p-toluenesulfonyloxy)ethane (1.1.16)
and base. ##STR158##
1.3.9.2 N,N',N"-Tris(2-aminoethyl)-1,4,7-triazacyclononane.
From 1.3.9.1 and HBr/acetic acid. ##STR159## 1.3.10 Synthesis of
Polyaza Ligands with Pendant Arms Containing Amide Groups.
1.3.10.1
N,N',N"-Tris(methylcarboxamide)-1,4,7-triazacyclononane.
From N, N',.sub.1
N"-Tris-(methoxycarboxymethyl)-1,4,7-triazacyclononane (1.3.6.2)
and ammonia. ##STR160##
1.3.10.2
N,N',N"-Tris[-N-n-butyl(methylcarboxamide)]-1,4,7-triazacyclononane.
From N,N',N"-Tris-(methoxycarboxymethyl)-1,4,7-triazacyclononane
(1.3.6.2) and butylamine. ##STR161##
1.3.10.3
N,N',N"-Tris[-N-n-phenyl(methylcarboxamide)]-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3), N-phenylchloroacetamide
(prepared from aniline and chloroacetyl chloride) and excess sodium
carbonate. ##STR162## 1.3.11 Synthesis of Polyaza Ligands with
Pendant Arms Containing Phenolic Groups.
1.3.11.1
4,7-Di-(2-hydroxy-benzyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane.
From 1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (1.1.20),
salicylaldehyde (excess) and H.sub.2 /PtO.sub.2. ##STR163##
1.3.11.2
4-(2-hydroxy-benzyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane.
From 1,4,7,10-tetrazabicyclo[5.5.2]tetradecane (1.1.20),
salicylaldehyde (1.5 equivalents) and H.sub.2 /PtO.sub.2.
##STR164##
1.3.11.3 Bis-(2,2'-dihydroxybiphenylmethylene) ethylene
diamine.
From ethylenediamine (1.1.0) and 2,2'-dihydroxy benzophenone
(commercially available) with removal of H.sub.2 O. ##STR165##
1.3.11.4 N,N'-Bis-(2,2'-dihydroxybiphenylmethyl) ethylene
diamine.
From 1.3.11.3 and sodium borohydride. ##STR166##
1.3.11.5 Bis-(2,4-dihydroxybiphenylmethylene) ethylenediamine.
From ethylenediamine (1.1.0) and 2,4-dihydroxy benzophenone
(commercially available) with removal of H.sub.2 O. ##STR167##
1.3.11.6 N,N'-Bis-(2,4-dihydroxybiphenylmethyl)
ethylenediamine.
From 1.3.11.5 and sodium borohydride. ##STR168##
1.3.11.7 N,N"-Bis-(2,2'-dihydroxybiphenylmethylene)diethylene
triamine.
From diethylene triamine (1.1.1) and 2,2'-dihydroxy benzophenone
with removal of H.sub.2 O. ##STR169##
1.3.11.8 N,N"-Bis-(2,2'-dihydroxybiphenylmethyl) diethylene
triamine.
From 1.3.11.7 and sodium borohydride. ##STR170##
1.3.11.9
Bis-(2,2'-dihydroxybiphenylmethylene)-1,3-diaminopropane.
From diaminopropane and 2,2'-dihydroxy benzophenone with removal of
H.sub.2 O. ##STR171##
1.3.11.10
N,N'-Bis-(2,2'-dihydroxybiphenylmethyl)-1,3-diaminopropane.
From and 1.3.11.9 and sodium borohydride. ##STR172##
1.3.11.11
N,N',N"-Tris(2-hydroxybenzyl)-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane, salicylaldehyde and H.sub.2
/PtO.sub.2. ##STR173## 1.3.12 Synthesis of Polyaza Ligands with
More Than One Species of Pendant Arm.
1.3.12.1 N-(p-Toluenesulfonyl)-N',
N"-bis(diethylphosphorylmethyl)-1,4,7-triazacyclononane.
From N-(p-toluenesulfonyl)-1,4,7-triazacyclononane dihydrobromide
(1.3.13.31), formaldehyde and diethyl phosphite. ##STR174##
1.3.12.2
N,N'-Bis(diethylphosphorylmethyl)-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3) trihydrobromide, one
equivalent formaldehyde and one equivalent of diethyl phosphite.
Purification of product by chromatography. ##STR175##
1.3.12.3
N,N'-Bis(dihydroxyphosphorylmethyl)-1,4,7-triazacyclononane.
From 1.3.12.2 and HCl. ##STR176##
1.3.12.4
N-(Carboxymethyl)-N,N'-bis(dihydroxyphosphorylmethyl)-1,4,7-triazacyclonon
ane.
From 1.3.12.3, chloroacetic and NaOH. ##STR177##
1.3.12.5
4-(2-Hydroxy-benzyl)-7-diethylphosphorylethyl-1,4,7,10-tetraazabicyclo[5.5
.2]tetradecane.
From 4-(2-hydroxybenzyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane
(1.3.11.2), diethyl phosphite and formaldehyde solution.
##STR178##
1.3.12.6
4-(2-hydroxy-benzyl)-7-phosphorylethyl-1,4,7,10-tetraazabicyclo[5.5.
2]tetradecane.
From 1.3.12.5 and HCl. ##STR179## 1.3.13 Miscellaneous Substituted
Polyaza Compounds.
1.3.13.1
1,2-Bis-(4,7-benzyloxycarbonyl-1,4,7-triazacyclononan-1-yl)ethane.
From 1,2-bis-(1,4,7-triazacyclononan-1-yl)ethane(1.1.28)
polyhydrobromide, potassium carbonate and benzyl chloroformate.
##STR180##
1.3.13.2
N-(p-Toluenesulfonyl)-N',N"-Bis-(benzyloxycarbonyl)-1,4,7-triazacyclononan
e.
From N-(p-toluenesulfonyl)-1,4,7-triazacyclononane dihydrobromide
(1.3.13.31), K.sub.2 CO.sub.3 and benzyl chloroformate.
##STR181##
1.3.13.3
N-(p-Toluenesulfonyl)-N"-benzyloxycarbonyl-1,4,7-triazacyclononane.
From
N-(p-toluenesulfonyl)-N',N"-bis(benzyloxycarbonyl)-1,4,7-triazacyclononane
(1.3.13.2) and trimethylsilyl iodide. ##STR182##
1.3.13.4
1,2-Bis[(1-p-toluenesulfonyl)-4-benzyloxycarbonyl-1,4,7-triazacyclonon-7-y
l]ethane.
From
1-(p-toluenesulfonyl)-4-benzyloxycarbonyl-1,4,7-triazacyclononane
(1.3.13.3), potassium carbonate and dibromoethane. ##STR183##
1.3.13.5 N,N',N"-Tris(phenylacetyl)-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3), diethyl
phenylacetylphosphonate[PhCH.sub.2 COP(O)(OEt).sub.2 ].
##STR184##
1.3.13.6 N,N',N"-Tris(2,3-Epoxypropyl-1,4,7-Triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3) and epibromohydrin.
##STR185##
1.3.13.7 N,N',N"-Tri-allyl-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3), sodium hydride and allyl
bromide. ##STR186##
1.3.13.8
N,N',N"-Tris(benzyloxycarbonyl)-1,4,7-triazacyclononane.
From 1,4,7-triazacyclononane (1.1.3), benzyl chloroformate and
sodium carbonate. ##STR187##
1.3.13.9 N,N'-Bis(benzyloxycarbonyl)-1,4,7-triazacyclononane.
From N,N',N"-tris(benzyloxycarbonyl)-1,4,7-triazacyclononane
(1.3.13.8) and iodotrimethylsilane. ##STR188##
1.3.13.10
N,N'-Bis(benzyloxycarbonyl)-N"-(2-bromoethyl)-1,4,7-triazacyclononane.
From N,N'-bis(benzyloxycarbonyl)-1,4,7-triazacyclononane
(1.3.13.9), dibromoethane and potassium carbonate. ##STR189##
1.3.13.11
N-p-Toluenesulfonyl-N',N"-ditrifluoroacetyl-1,4,7-triazacyclononane.
From N-p-toluenesulfonyl-1,4,7-triazacyclononane (1.3.13.31),
potassium carbonate and trifluoroacetic anhydride. ##STR190##
1.3.13.12
N-p-Toluenesulfonyl-N'-benzyl-1,4,7-triazacyclononane.
From N-(p-toluenesulfonyl-1,4,7-triazacyclononane (1.3.13.31),
sodium hydride and benzyl bromide. ##STR191##
1.3.13.13
N-p-Toluenesulfonyl-N',N"-dibenzyl-1,4,7-triazacyclononane.
From N-(p-toluenesulfonyl-1,4,7-triazacyclononane (1.3.13.31),
sodium hydride and benzyl bromide. ##STR192##
1.3.13.14
1,2-Bis(N-p-toluenesulfonyl-N'-benzyl)-1,4,7-triazacyclononan-1-yl)
ethane.
From N-p-toluenesulfonyl-N'-benzyl-1,4,7-triazacyclononane
(1.3.13.12), dibromoethane and potassium carbonate. ##STR193##
1.3.13.15
1,2-Bis(N,N'-ditrityl-1,4,7-triazacyclononan-1-yl)ethane.
From 1,2-Bis(1,4,7-triazacyclononane)ethane (1.1.28), potassium
carbonate and trityl chloride. ##STR194##
1.3.13.16 Spiro
[4,8]-4,7-di-p-toluenesulfonyl-4,7-diaza-1-azotridecane halide.
From 1,4,7-triazacyclononane-N,N'-di-p-toluenesulfonyl hydrobromide
(1.3.13.32), diiodobutane and potassium carbonate. ##STR195##
1.3.13.17
Tetrakis(p-toluenesulfonyl)-1,4,7,10-tetraazacyclotetradecane.
From N,N',N"-tris(p-toluenesulfonyl)diethylenetriamine (1.3.13.18),
potassium carbonate and
bis(2-p-toluenesulfonyloxyethyl)-N-(p-toluenesulfonyl) amine
(1.3.13.19). ##STR196##
1.3.13.20
1,7-Bis(p-toluenesulfonyl)-4-benzyl-1,4,7-triazaheptane.
From benzylamine,
(2-p-toluenesulfonyoxyl)-N-(p-toluenesulfonyl)-ethylamine
(1.3.13.21) and potassium carbonate. ##STR197##
1.3.13.22 N-Trityidiethanolamine.
From diethanolamine and trityl chloride. ##STR198##
1.3.13.23 N-Trityl-bis(2-p-toluenesulfonyloxyethyl)amine.
From N-trityldiethanolamine and p-toluenesulfonyl chloride.
##STR199##
1.3.13.24
1,7-di-(p-toluenesulfonyl)-4-benzyl-10-trityl-1,4,7,10-tetraazacyclotetrad
ecane.
From 1,7-di-p-toluenesulfonyl-4-benzyl-1,4,7-triazaheptane
(1.3.13.20), sodium hydride and
N-trityl-di-p-toluenesulfonyldiethanolamine (1.3.13.23).
##STR200##
1.3.13.25
1,7-Di-(p-toluenesulfonyl)-1,4,7,10-tetraazacyclotetradecane.
From
1,7-di-(p-toluenesulfonyl)-4-benzyl-10-trityl-1,4,7,10-tetraazacyclotetrad
ecane (1.3.13.24) reduced by H.sub.2 and Pd/C. ##STR201##
1.3.13.26
1,7-Di-(p-toluenesulfonyl)-4-benzyl-1,4,7,10-tetraazacyclotetradecane.
From reduction of 1.3.13.24. ##STR202##
1.3.13.27
1,2-Bis-(4,10-di-p-toluenesulfonyl-7-benzyl-1,4,7,10-tetraazacyclotetradec
an-1-yl)ethane.
From 1.3.13.26 and dibromoethane. ##STR203##
1.3.13.28 1,5,9,13-Tetraazatetracyclo[6,6,2,0.sup.1,15,0.sup.8,16
]hexadecane
From 1.1.6 and glyoxaldehyde. ##STR204##
1.3.13.29 4,7-Diallyl-1,4,7-triazabicyclo[7,4,0]tridecane.
From 1,4,7-triazabicyclo[7,4,0]tridecane trihydrobromide (1.1.14),
sodium hydride and allyl bromide. ##STR205##
1.3.13.30 N-p-Toluenesulfonyl-1,4,7-triazacyclononane
dihydrobromide.
From N,N',N"-Tris(p-toluenesulfonyl)-1,4,7-triazacyclononane
(1.3.13.31) prepared from 1.3.13.18, dibromoethane and base) and
HBr/acetic acid. ##STR206##
1.3.13.32 N,N'-Di-p-Toluenesulfonyl-1,4,7-triazacyclononane
hydrobromide.
a) From N, N',N"-tris(p-toluenesulfonyl)-1,4,7-triazacyclononane
(1.3.13.31 and HBr/acetic acid as the hydrobromide salt.
##STR207##
1.3.13.33 N,N,N',N'-Tetraallylethylenediamine.
From ethylenediamine, sodium carbonate and allyl bromide.
##STR208##
1.3.13.34
4,7,13-Tris(p-toluenesulfonyl)-1,4,7,10-13-pentaazabicyclo[8.5.2]
heptadecane.
From 1,4,7,10,13-pentaazabicyclo[8.5.2]heptadecane (1.1.26),
potassium carbonate and p-toluenesulfonyl chloride. ##STR209##
1.3.13.35
1,2-Bis(4-p-toluenesulfonyl-1,4,7-triazacyclonon-1-yl)ethane.
From
1,2-bis(4,7-di-p-toluenesulfonyl-1,4,7-triazacyclonon-1-yl)ethane
(1.1.30) and sulphuric acid. ##STR210##
1.3.13.36
N,N'-(Di-p-toluenesulfonyl)-N"-benzyl-1,4,7-Triazacyclononane.
a) From N,N"-(p-toluenesulfonyl)-4-benzyl diethylenetriamine
(1.3.13.20), sodium hydride and ethylene glycol
di-p-toluenesulfonate (1.1.12).
b) From N,N'-bis(p-toluenesulfonyl)-1,4,7-triazacyclononane
(1.3.13.32), sodium hydride and benzyl bromide. ##STR211##
1.3.13.37
N-(p-Toluenesulfonyl)-N'-trityl-1,4,7-triazacyclononane.
From N-(p-toluenesulfonyl-1,4,7-triazacyclononane dihydrobromide
(1.3.13.30), sodium hydride and trityl chloride. ##STR212##
1.3.13.38 Hexakis(allyl) triethylenetetramine.
From triethylenetetramine (1.1.2), sodium carbonate and allyl
bromide. ##STR213##
1.3.13.39
4,7-diallyl-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane.
From 1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (1.1.4), allyl
bromide and base. ##STR214##
Example 2
This example illustrates the preparation of metal complexes using
the chelating agents (ligands) described in Example 1.
2.1 Synthesis of Metal Complexes
Water soluble salts of metals and compounds described in the above
examples were heated in water or alcohol solvents followed by base
addition to neutral or basic pH. Alternately, an excess of these
metals in the form of their corresponding insoluble oxides or
hydroxides was heated with the acid form of the compounds described
in preceding sections until complexation was complete, followed by
filtration to remove uncomplexed excess metal oxide or hydroxide.
In either case complex formation was verified by chromatography.
Employing these methods the following complexes were
synthesized:
2.1.1 Iron (III) complexes with the following Compounds:
2.1.1.1. 1,2-Bis(1,4,7-triazabicyclononan-1-yl)ethane (1.1.29)
2.1.1.2.
N,N',N"-Tris(2-hydroxy-3-isopropoxypropyl)-1,4,7-triazacyclononane
(1.3.1.1)
2.1.1.3. (R, R, R)
N,N',N"-Tris(2-hydroxy-3-isopropoxypropyl)-1,4,7-triazacyclononane
(1.3.1.2).
2.1.1.4. (S, S, S)
N,N',N"-Tris(2-hydroxy-3-isopropoxypropyl)-1,4,7-triazacyclononane
(1.3.1.3).
2.1.1.5.
N,N',N"-Tris(2-hydroxy-3-isobutoxypropyl)-1,4,7-triazacyclononane(1.3.1.4)
.
2.1.1.6. (R, R, R)
N,N',N"-Tris(2-hydroxy-3-isobutoxypropyl)-1,4,7-triazacyclononane
(1.3.1.5).
2.1.1.7.
N,N',N"-Tris(2-hydroxy-3-methoxypropyl)-1,4,7-triazacyclononane(1.3.1.6).
2.1.1.8.
N,N',N"-Tris(2,3-dihydroxypropyl)-1,4,7-triazacyclononane(1.3.1.7).
2.1.1.9.
N,N',N"-Tris(2-hydroxy-3-allyloxypropyl)-1,4,7-triazacyclononane(1.3.1.9).
2.1.1.10.
N,N',N"-Tris(2-hydroxy-3-phenoxypropyl)-1,4,7-triazacyclononane(1.3.1.10
).
2.1.1.11.
N,N',N"-Tris(2-hydroxy-2,2-diethoxymethylene)ethyl-1,4,7-triazacyclononane
(1.3.1.11).
2.1.1.12.
N,N',N"-Tris(2-hydroxy-2,2-dimethoxymethyl)ethyl-1,4,7-triazacyclononane
(1.3.1.12).
2.1.1.13.
N,N',N"-Tris(2-hydroxy-2,2-diisopropyloxymethyl)ethyl-1,4,7-triazacyclonon
ane (1.3.1.13).
2.1.1.14.
N,N',N"-Tris[2-hydroxy-bis(2-furfurylmethyl)ethyl]-1,4,7-triazacyclononane
(1.3.1.14).
2.1.1.15.
N,N',N"-Tris(3-hydroxy-1,5-dioxacycloheptyl-3-methyl)-1,4,7-triazacyclonon
ane (1.3.1.15).
2.1.1.16.
N,N',N"-Tris[(3-Hydroxy-7,7-dimethyl-1,5-dioxacyclooct-3-yl)-methyl]-1,4,7
-triazacyclononane (1.3.1.16).
2.1.1.17.
N,N',N"-Tris[(3-hydroxy-7-methyl-1,5-dioxacyclohept-3-yl)methyl]-1,4,7-tri
azacyclononane (1.3.1.17).
2.1.1.18.
N,N',N"-Tris[(3-hydroxy-6,6,7,7-tetramethyl-1,5-dioxacyclohept-3-yl)methyl
]-1,4,7-Triazacyclononane (1.3.1.18).
2.1.1.19. N,N',N"-Tris[(3-hydroxy-benzo[b]-1,5-dioxacycloheptyl
)methyl]1,4,7-triazacyclononane (1.3.1.1 9).
2.1.1.20.
N,N',N"-Tris[(3-hydroxy-1,5-dioxacyclooctan-3-yl)methyl]-1,4,7-triazacyclo
nonane (1.3.1.20).
2.1.1.21. N,N',N"-Tris[(4-fluoro-2-hydroxy-3-isopropyl-4-methyl
)pentyl]-1,4,7- triazacyclononane (1.3.1.22).
2.1.1.22. N,N',N"-Tris-[2-hydroxy-3-(1-fluoroethyl
)-4-hydroxypentyl]-1,4,7-triazacyclononane (1.3.1.23).
2.1.1.23.
N,N',N"-Tris[2-hydroxy-2-(1-fluoroethyl)-2-(1-methoxyethyl)ethyl]-1,4,7-tr
iazacyclononane (1.3.1.24).
2.1.1.24.
N,N',N"-Tris(2-hydroxy-2-ethyl-3-methoxybutyl)-1,4,7-triazacyclononane
(1.3.1.25).
2.1.1.25.
N,N',N"-Tris[(2,3-dihydroxy-2-ethyl)butyl-1,4,7-triazacyclononane
(1.3.1.26).
2.1.1.26.
N,N',N"-Tris[2-hydroxy-2,2-bis(1-fluoroethyl)ethyl]-1,4,7-triazacyclononan
e (1.3.1.27).
2.1.1.27.
N,N',N"-Tris[2-hydroxy-2,2-bis(1-methoxyethyl)ethyl]-1,4,7-triazacyclonona
ne (1.3.1.28).
2.1.1.28.
N,N',N"-Tris[(3,3-dimethyl-2-hydroxy)butyl]-1,4,7-triazacyclononane
(1.3.1.29).
2.1.1.29.
N,N',N"-Tris(2-hydroxycyclohexan-1-yl)-1,4,7-triazacyclononane
(1.3.1.33).
2.1.1.30.
N,N',N",N"'-Tetrakis(2,3-dihydroxypropyl)-1,4,7,10-tetraazacyclotetradecan
e (1.3.1.38).
2.1.1.31.
4,10-Bis(2-hydroxypropyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane
(1.3.1.39).
2.1.1.32.
4,10-Bis-(2-hydroxyethyl)-1,4,7,10-tetrazabicyclo[5.5.2]tetradecane
(1.3.1.40).
2.1.1.33.
4,10-Bis-(2,3-dihydroxypropyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane
(1.3.1.42).
2.1.1.34.
N,N',N"-Tris[(2,4-dihydroxy-3-isopropyl-4-methyl)pentyl]-1,4,7-triazacyclo
nonane (1.3.1.54).
2.1.1.35.
N,N',N"-Tris(2-hydroxy-bis(2,2-dihydroxymethyl)ethyl]-1,4,7-triazacyclonon
ane (1.3.1.55).
2.1.1.36. N,N',N"-Tris(dihydroxyphosphoryl mono butyl
ester)methyl-1,4,7-triazacyclononane (1.3.2.2).
2.1.1.37. N,N',N"-Tris(dihydroxyphosphorylmethyl monoethyl
ester)-1,4,7-triazacyclononane (1.3.2.4).
2.1.1.38. N,N',N"-Tris(dihydroxyphosphorylmethyl monooctyl
ester)-1,4,7-triazacyclononane (1.3.2.6).
2.1.1.39. N,N',N"-Tris(dihydroxyphosphorylmethyl monoisobutyl
ester)-1,4,7-triazacyclononane (1.3.2.8).
2.1.1.40.
1,2-Bis(N,N'-bis(dihydroxyphosphorylmethyl)-1,4,7-triazacyclononan-1-yl)et
hane (1.3.3.1).
2.1.1.41.
1,2-Bis(N,N'-bis(dihydroxyphosphorylmethyl)-1,4,7-triazacyclononan-1-yl)pr
opane (1.3.3.2).
2.1.1.42.
4,10-Bis(dihydroxyphosphorylmethyl)-1,4,7,10-tetraazabicyclo[5.5.2]
tetradecane.
2.1.1.43.
4,7,13-Tris(dihydroxyphosphorylmethyl)-1,4,7,10,13-pentaazabicyclo[8.5.2]h
eptadecane (1.3.3.4).
2.1.1.44.
N,N',N"-Tris(dihydroxyphosphoryIethyl)-1,4,7-triazacyclononane(1.3.3.5).
2.1.1.45.
N',N",N"',N""-Tetrakis(dihydroxyphosphorylethyl)-1,4,7,10-tetraazacyclodod
ecane (1.3.3.6).
2.1.1.46.
4,10-Bis(dihydroxyphosphorylethyl)-1,4,7,10-tetraazabicyclo[5.5.2]
tetradecane (1.3.3.7).
2.1.1.47.
N,N',N"-Tris[(N-methyl-N-hydroxycarbamoyl)methyl]-1,4,7-triazacyclononane
(1.3.5.2).
2.1.1.48.
N,N',N"-Tris[(N-isopropyl-N-hydroxycarbamoyl)methyl]-1,4,7-triazacyclonona
ne (1.3.5.4).
2.1.1.49.
N,N',N"-Tris[(N-t-butyl-N-hydroxycarbamoyI)methyl]-1,4,7-triazacyclononane
(1.3.5.6).
2.1.1.50.
N,N',N"-Tris[(N-hydroxycarbamoyl)methyl]-1,4,7-triazacyclononane(1.3.5.8).
2.1.1.51.
N,N',N"-Tris[(N-methoxycarbamoyl)methyl]-1,4,7-triazacyclononane(1.3.5.9).
2.1.1.52.
4,10-Bis[(N-hydroxy-N-methylcarbamoyl)methyl]-1,4,7,10-tetraazabicyclo[5.5
.2]tetradecane (1.3.5.11)
2.1.1.53.
N,N',N"-Tris[(1-hydroxy-2-pyrrolidon-5-yl)methyl]-1,4,7-triazacyclononane
(1.3.5.13).
2.1.1.54.
N,N',N"-Tris[(1-hydroxy-2-pyrrolidon-5-yl)methyl]-1,4,7-triazacyclononane
(1.3.5.13).
2.1.1.55. N,N',N"-Tris(carboxymethyl)-1,4,7-triazacyclononane
(1.3.6.1).
2.1.1.56.
1,2-Bis-(4,7-carboxymethyl-1,4,7-triazacyclononan-1-yl)ethane(1.3.6.7).
2.1.1.57. N,N',N"-Tris(carboxyethyl)-1,4,7-triazacyclononane
(1.3.6.10).
2.1.1.58.
4,10-Bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane
(1.3.6. 12).
2.1.1.59.
N,N',N"-Tris(2,2-dimethoxyethyl)-1,4,7-triazacyclononane(1.3.7.1).
2.1.1.60. N,N',N"-Tris(pyrrol-2-yl-methyl)-1,4,7-triazacyclononane
(1.3.8.1).
2.1.1.61. N,N',N"-Tris[N-n-butyl (carbamoylmethyl)]
-1,4,7-triazacyclononane(1.3.10.2).
2.1.1.62.
N.N',N"-Tris[N-phenyl(carbamoylmethyl)]-1,4,7-triazacyclononane(1.3.10.3).
2.1.1.63.
4,7-Bis(2-hydroxybenzyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane
(1.3.11.1).
2.1.1.64. N,N'-Bis-(2,4-dihydroxybiphenylmethyl)ethylenediamine
(1.3.11.6).
2.1.1.65.
N,N'-Bis-(2,2'-dihydroxybiphenylmethyl)diethylenetriamine(1.3.11.8).
2.1.1.66.
N,N'-Bis-(2,2'-dihydroxybiphenylmethyl)-1,3-diaminopropane(1.3.11.10).
2.1.1.67.
N,N',N"-Tris(2-hydroxybenzyl)-1,4,7-triazacyclononane(1.3.11.11).
2.1.1.68.
N,N'-bis(dihydroxyphosphorylmethyl)-1,4,7-Triazacyclononane(1.3.12.3).
2.1.1.69.
N-(carboxymethyl)-N',N"-bis(dihydroxyphosphorylmethyl)-1,4,7-triazacyclono
nane (1.3.12.4).
2.1.2 Gadolinium (III) complexes with the following chelators:
2.1.2.1.1,2-Bis(N,N'-bis(dihydroxyphosphorylmethyl)-1,4,7-triazacyclononan-
1-yl)ethane (1.3.1.13).
2.1.2.2.
1,2-Bis(N,N'-bis(dihydroxyphosphrylmethyl)-1,4,7-triazacyclononan-1-yl)pro
pane (1.3.3.2).
2.1.2.3.
4,7,13-Tris(dihydroxyphosphorylmethyl)-1,4,7,10,13-pentaazabicyclo[8.5.2]h
eptadecane (1.3.3.4).
2.1.2.4. N,N',N",
N"'-Tetrakis(dihydroxyphosphorylethyl)-1,4,7,10-tetraazacyclododecane
(1.3.3.6).
2.1.2.5.
N,N',N"-Tris[2-dihydroxyphosphoryl-1-hydroxy)ethyl]-1,4,7-triazacyclononan
e (1.3.4.3).
2.1.2.6.
1,2-Bis-(4,7-carboxymethyl-1,4,7-triazacyclononan-1-yl)ethane(1.3.6.7).
2.1.2.7.
N,N'-Bis-(2,2'-dihydroxybiphenylmethyl)ethylenediamine(1.3.11.4).
2.1.2.8. N,N'-Bis-(2,4-dihydroxybiphenylmethyl)ethylenediamine
(1.3.11.6).
2.1.3 Copper (II) complexes with the following Compounds:
2.1.3.1.1,4,7,10-Tetraazabicyclo[5.5.2]tetradecane (1.1.22).
2.1.3.2.
N,N',N"-Tris(2-hydroxy-2,2-diisopropyloxymethyl)ethyl-1,4,7-triazacyclonon
ane (1.3.1.13).
2.1.3.3. 4,10-Bis(2-Hydroxypropyl)-1,4,7,10-tetraazabicyclo[5.5.2]
tetradecane (1.3.1.39).
2.1.3.4.
4,7-Bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane(1.3.6.8)
.
2.1.3.5.
4,10-Bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane
(1.3.6.12).
2.1.3.6.
4,7-Bis(2-hydroxybenzyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane
(1.3.1 1.1).
2.1.4 Zinc (II) complexes with the following Compounds:
2.1.4.1.
N,N',N"-Tris(2-hydroxy-2,2-diisopropyloxymethyl)ethyl-1,4,7-triazacyclonon
ane (1.3.1.13).
2.1.4.2.
4,7-Bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane(1.3.6.8)
.
2.1.4.3.
4,10-Bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane
(1.3.6.12).
2.1.4.4.
4,7-Bis(2-hydroxybenzyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane
(1.3.1 1.1).
2.1.5 Manganese (II) complexes with the following Compounds:
2.1.5.1.
4,10-Bis(dihydroxyphosphorylmethy)-1,4,7,10-tetraazabicyclo [5.5.2]
tetradecane (1.3.3.3).
2.1.5.2.
4,7,13-Tris(dihydroxyphosphorylmethyl)-1,4,7,10,13-pentaazabicyclo
[8.5.2]heptadecane (1.3.3.4).
2.1.5.3.
1,2-Bis-(4,7-carboxymethyl-1,4,7-triazacyclononan-1-yl)ethane(1.3.6.7).
2.1.5.4.
4,7-Bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane(1.3.6.8)
.
2.1.6 Cadmium (II) complexes with the following Compounds:
2.1.6.1
4,7,13-Tris(dihydroxyphosphorylmethyl)-1,4,7,10,13-pentaazabicyclo[8.5.2]h
eptadecane (1.3.3.4).
2.1.7 Lead (II) complexes with the following Compounds:
2.1.7
4,7,13-Tris(dihydroxyphosphorylmethyl)-1,4,7,10,13-pentaazabicyclo[8.5.2]h
eptadecane (1.3.3.4).
2.1.8 Mercury (II) complexes with the following Compounds:
2.1.8.1
4,7,13-Tris(dihydroxyphosphorylmethyl)-1,4,7,10,13-pentaazabicyclo[8.5.2]h
eptadecane (1.3.3.4).
2.1.9 Nickel (II) complexes with the following Compounds:
2.1.9.1
4,7-Bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane
(1.3.6.8).
2.1.10 Calcium (II) complexes with the following Compounds:
2.1.10.1.
4,10-Bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane
(1.3.6. 12).
2.1.10.2.
4,7-Bis(2-hydroxybenzyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane
(1.3.11.1).
2.1.11 Magnesium (II) complexes with the following Compounds:
2.1.11.1.
4,10-Bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane
(1.3.6. 12).
2.1.11.2.
4,7-Bis(2-hydroxybenzyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane
(1.3.11.1).
2.2 Synthesis of Radioactive Complexes
Water soluble salts of radioisotopes of iron (III) and gadolinium
or manganese (II) (e.g., chloride salts of Fe-59, Gd-153) and
chelators described in Examples 1.3 were heated in water, alcohol
or DMSO solvents followed by base addition to achieve neutral or
basic pH. Complex formation was verified by radiochromatography.
Employing this method the following complexes were synthesized.
2.2.1 Complexes of Fe-59
2.2.1.1.
N,N',N"-Tris(2-hydroxy-3-isopropoxypropyl)-1,4,7-triazacyclononane
(1.3.1.1).
2.2.1.2. (R, R, R)
N,N',N"-Tris(2-hydroxy-3-isopropoxypropyl)-1,4,7-triazacyclononane
(1.3.1.2).
2.2.1.3. (S, S, S)
N,N',N"-Tris(2-hydroxy-3-isopropoxypropyl)-1,4,7-triazacyclononane
(1.3.1.3).
2.2.1.4. (R, R, R)
N,N',N"-Tris(2-hydroxy-3-isobutoxypropyl)-1,4,7-triazacyclononane
(1.3.1.5).
2.2.1.5.
N,N',N"-Tris(2-hydroxy-3-methoxypropyl)-1,4,7-triazacyclononane
(1.3.1.6).
2.2.1.6. N,N',N"-Tris(2,3-dihydroxypropyl)-1,4,7-triazacyclononane
(1.3.1.7).
2.2.1.7.
N,N',N"-Tris(2-hydroxy-2,2-diisopropyloxymethyl)ethyl-1,4,7-triazacyclonon
ane (1.3.1.13).
2.2.1.8.
N,N',N"-Tris(3-hydroxy-1,5-dioxacycloheptyl-3-methyl)-1,4,7-triazacyclonon
ane (1.3.1.15).
2.2.1.9.
N,N',N"-Tris[(3-hydroxy-7,7-dimethyl-1,5-dioxacyclooct-3-yl)-methyl]-1,4,7
-triazacyclononane (1.3.1.16).
2.2.1.10.
N,N',N"-Tris[(3-hydroxy-6,6,7,7-tetramethyl-1,5-dioxacyclohept-3-yl)methyl
]-1,4,7-triazacyclononane (1.3.1.18).
2.2.1.11.
N,N',N"-Tris[(3-hydroxy-1,5-dioxacyclooctane-3-yl)methyl]-1,4,7-triazacycl
ononane (1.3.1.20).
2.2.1.12.
N,N',N'-Tris(2-hydroxy-2-methylpropyl)-1,4,7-triazacyclononane
(1.3.1.21).
2.2.1.13.
N,N',N"-Tris[(2,3-dihydroxy-2-ethylbutyl)]-1,4,7-triazacyclononane
(1.3.1. 26).
2.2.1.14.
N,N',N"-Tris[2-hydroxy-2,2-bis(1-methoxyethyl)ethyl]-1,4,7-triazacyclonona
ne (1.3.1.28).
2.2.1.15. N,N',N"-Tris(2-hydroxypropyl)-1,4,7-triazacyclononane
(1.3.1.30).
2.2.1.16. N,N',N"-Tris(dihydroxyphosphorylmethyl monobutyl
ester)-1,4,7-triazacyclononane (1.3.2.2).
2.2.1.17. N,N',N"-Tris(dihydroxyphosphorylmethyl monoethyl
ester)-1,4,7-triazacyclononane (1.3.2.4).
2.2.1.18.
4,10-Bis(dihydroxyphosphorylmethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetrade
cane (1.3.3.3).
2.2.1.19.
N,N',N"-Tris(dihydroxyphosphorylethyl)-1,4,7-triazacyclononane
(1.3.3.5).
2.2.1.20.
N,N',N",N"'-Tetrakis(dihydroxyphosphorylethyl)-1,4,7,10-tetraazacyclododec
ane (1.3.3.6).
2.2.1.21.
4,10-Bis(dihydroxyphosphorylethyl)-1,4,7,10-tetraazabicyclo[5.5.2])
tetradecane (1.3.3.7).
2.2.1.22.
N,N',N"-Tris{[(diethylphosphoryl)-.alpha.-hydroxy]ethyl}-1,4,7-triazacyclo
nonane (1.3.4.2).
2.2.1.23.
N,N',N"-Tris[(N-methyl-N-hydroxycarbamoyl)methyl]-1,4,7-triazacyclononane
(1.3.5.2).
2.2.1.24.
N,N',N"-Tris[(N-isopropyl-N-hydroxycarbamoyl)methyl]-1,4,7-triazacyclonona
ne (1.3.5.4).
2.2.1.25.
N,N',N"-Tris[(N-t-butyl-N-hydroxycarbamoyl)methyl]-1,4,7-triazacyclononane
(1.3.5.6).
2.2.1.26.
1,2-Bis-(4,7-carboxymethyl-1,4,7-triazacyclononan-1-yl)ethane
(1.3.6.7).
2.2.1.27. N,N',N"-Tris(carboxyethyl)-1,4,7-triazacyclononane
(1.3.6.10).
2.2.1.28.
N,N',N"-Tris[N-n-butyl(methylcarboxamide)]-1,4,7-triazacyclononane
(1.3.10 .2).
2.2.1.29.
4,7-Bis(2-hydroxybenzyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane
(1.3.11.1).
2.2.1.30.
N,N'-Bis(dihydroxyphosphorylmethyl)-1,4,7-triazacyclononane
(1.3.12.3).
2.2.1.31.
N-(carboxymethyl)-N',N"-bis(dihydroxyphosphorylmethyl)-1,4,7-triazacyclono
nane (1.3.12.4).
2.2.2 Complexes of Mn-54
2.2.2.1
4,7-Bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane
(1.3.6.8).
Example 3
This example illustrates the ability of the chelating agents
described above to inhibit cell replication in vitro.
3.1: Inhibition of Bacterial Replication
This example demonstrates the ability of a representative example
of the claimed ligands to inhibit replication of various bacteria
in vitro.
N,N',N"-tris(dihydroxyphosphorylmethyl)-1,4,7-triazacyclononane was
prepared as described in Example 1C in U.S. Pat. No. 5,236,695.
Studies were performed to determine its ability to inhibit
bacterial growth. For Streptococcus hemolyticus, Listeria
monocytogenes, Enterobacter cloacae and Klebsiella pneumoniae the
minimum inhibitory concentration was determined to be 0.15 mM/L.
For Enterococcus fecalis, Pseudomonas aeruginosa and Acinobacter
anitratus the minimum inhibitory concentration was determined to be
0.3 mM/L.
3.2: Inhibiton of Mycotic Cell Replication in Vitro
This example demonstrates the ability of a representative example
of the claimed ligands to inhibit mycotic (fungal) cell replication
in vitro.
N,N',N"-tris(dihydroxyphosphorylmethyl)-1,4,7-triazacyclononane was
prepared as described in Example 1C in U.S. Pat. No. 5,236,695.
Studies were performed to determine its ability to inhibit growth
of mycotic (fungal) organisms.
For Microsporum canis the minimum inhibitory concentration was
0.233 mM/L or less. For Candida albicans and Trichophyton rubrum
the minimal inhibitory concentration was 2.33 mM/L. For
Trichophyton mentagrophytes, Trichophyton tonsuras and Trichophyton
violaceum the minimal inhibitory concentration was 23.3 mM/L.
3.3: Inhibition of Mammalian Cell Replication in Vitro
This example demonstrates the ability of representative examples of
the claimed ligands to inhibit mammalian cell replication in
vitro.
N,N',N"-tris(dihydroxyphosphorylmethyl)-1,4,7-triazacyclononane was
prepared as described in Example 1C in U.S. Pat. No. 5,236,695.
Concentrations of this ligand of 0.009 mM/L inhibited the growth of
both BGM cells (a continuous cell line of monkey origin) and HFF
cells (human foreskin fibroblasts).
N N',N"-Tris(carboxymethyl)-1,4,7-Triazacyclononane (Example
1.3.6.1) at a concentration of 0.009 mM/L inhibited BGM cell growth
and a concentration of 0.019 mM/L inhibited HFF cell growth.
N,N',N"-Tris(ethoxycarbonylmethyl)-1,4,7-Triazacyclononane (Example
1.3.6.13) at a concentration of 0.04 mM/L inhibited BGM cell growth
and at a concentration of 0.16 mM/L inhibited HFF cell growth.
Diethylene triamine penta acetic acid at a concentration of 0.075
mM/L inhibited BGM cell growth and at 0.3 mM/L inhibited HFF cell
growth.
Example 4
This example demonstrates the relative lack of toxicity of a
representative example of the claimed ligands toward
nonproliferating mammalian cells in vitro.
N,N',N"-tris(dihydroxyphosphorylmethyl)-1,4,7-triazacyclononane was
prepared as described in Example 1C in U.S. Pat. No. 5,236,695.
A concentration of 0.3 mM of this agent was added to mature,
nonreplicating cultures of HFF (human foreskin fibroblasts) kept in
maintenance media and no effect on the resting cells was observed
over a five-day period of observation.
Example 5
This example illustrates the low in vivo toxicity of a
representative ligand administer intravenously to mice.
Over 50% of mice receiving 4.0 mM/kg intravenously of the sodium
salt of
N,N',N"-tris-(dihydroxyphosphorylmethyl)-1,4,7-triazacyclononane
(Example 1C in U.S. Pat. No. 5,236,695) as a single intravenous
dose survived for over 14 days following such administration
demonstrating that the acute LD50 of this agent is in excess of 4
mM/kg. This in vivo LD50 toxicity dose results in an instantaneous
in vivo concentration which is orders of magnitude greater than the
dose of this agent which inhibits mammalian cell replication in
vitro (0.009 mM/L).
Example 6
This example demonstrates the relatively low subacute toxicity of a
representative ligand administered intravenously in repeated doses
to rats.
Ten male Sprague Dawley rats 29 days old and weighing between 73.4
and 87.8 grams at the beginning of the experiment were randomized,
employing the block stratification method, into two groups
consisting of five rats each. On each of days 1, 2, 3, 6, 7, 8, 9,
10, 13 and 14 of the experiment one set of rats received an
intravenous dose of N,N',N"-tris
(dihydroxyphosphorylmethyl)-1,4,7-triazacyclononane (Example 1C in
U.S. Pat. No. 5,236,695) equal to 0.05 millimoles per kg of initial
body weight (experimental group) while the other group received an
equivalent volume of normal saline solution. The weights of the
animals were recorded three times per week and the animals were
sacrificed on the 28th day, major organs removed and weighed and
tissues removed for microscopic examination. There was no
statistically significant difference in weight or rate of weight
gain between the experimental and control group of rats, either
during the period of injections or in the two-week post-injection
period. There were no differences observed between the weights of
major organs of the experimental vs. the control group. There were
no differences between the tissues of the experimental vs. the
control group upon microscopic examination of the tissues obtained
at the time of necropsy.
Example 7
This example illustrates the in vivo distribution of radioisotopic
complexes
Examples of the in vivo distribution of radioisotopic complexes of
representative ligands are herein disclosed which demonstrate the
ability of these agents to be predominantly excreted by the
kidneys, or the liver, or to pass across cell membranes and
accumulate in the intracellular fluid space (e.g. in heart muscle).
Those skilled in the art will recognize that a similar in vivo
distribution can be anticipated from non-radioisotopic paramagnetic
complex species.
In the following examples certain radioisotopic complexes of the
subject ligands were administered intravenously to mice and the
tissue distribution of the radioisotopic complexes was measured by
detection of radioisotopic content of tissues removed at
necropsy.
6.1: Example of a Complex which is Predominantly Excreted by the
Kidneys in the Urine
The iron-59 labeled complex of N,N',N'-tris(2,3-dihydroxy
propyl)-1,4,7-triazacyclononane (Example 2.2.1.6) was administered
intravenously to mice and at necropsy the tissue distribution of
radioactivity showed predominant concentration of the agent in the
kidneys and urine.
6.2: Example of a Complex Which is Predominantly Excreted by the
Liver in the Bile.
The iron-59 complex of
N,N',N"-tris(2'-hydroxy-3-iso-propoxypropyl)-1,4,7-triazacyclononane
(Example 2.2.1.1) was administered intravenously to mice and at
necropsy the tissue distribution of radioactivity showed
predominant concentration of the agent in the liver, bile and
intestinal contents.
6.3: Example of a Complex which Rapidly Passes Accross Cell
Membranes and Enters the Intracellular Fluid Space
The iron-59 complex of
N,N',N"-tris[2-hydroxy-(2,2-diisopropyloxymethyl)ethyl]-1,4,7-triazacyclon
onane (Example 2.2.1.7) was administered intravenously to mice and
at necropsy the tissue distribution of activity was consistent with
an intracellular as well as extracellular fluid distribution.
Within the first five minutes following agent administration the
concentration of activity in the heart was greater than that of
mixed venous blood indicating rapid equilibration of the agent
across myocardial cell membranes. The liver concentrated the agent
and excreted it into the bile.
* * * * *